WO2007028145A2

WO2007028145A2 - Agents and methods for reducing protein tyrosine phosphatase 1b activity in the central nervous system

Info

Publication number: WO2007028145A2
Application number: PCT/US2006/034467
Authority: WO
Inventors: Louis Herlands
Original assignee: Dara Biosciences, Inc.
Priority date: 2005-09-02
Filing date: 2006-09-01
Publication date: 2007-03-08
Also published as: WO2007028145A3

Abstract

The present invention provides pharmaceutical compositions and methods for administration to the central nervous system to reduce protein tyrosine phosphatase 1B (PTP1B) activity, reduce peripheral glucose concentrations, reduce glucose production, reduce lipid, triglyceride and/or cholesterol levels (e.g., in blood, plasma or serum), and/or food intake, and/or to treat a metabolic disorder such as diabetes mellitus (e.g., type I or type II), metabolic syndrome, hyperglycemia, insulin resistance, glucose intolerance and/or obesity, and/or to treat disorders such as leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, amenorrhea, cancer (including tumor forming cancers), neurodegenerative disease, and/or polycystic ovary syndrome. Also provided is a delivery device comprising a pharmaceutical composition of the invention.

Description

Attorney Docket No. 9442-27WO

AGENTS AND METHODS FOR REDUCING PROTEIN TYROSINE PHOSPHATASE 1 B ACTIVITY IN THE CENTRAL NERVOUS SYSTEM

RELATED APPLICATION INFORMATION

This application claims the benefit of United States Provisional Application Serial. Nos. 60/714,062 filed September 2, 2006 and United States Application Serial No. 60/785,965, filed March 24, 2006, the disclosures of which are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention is directed to compositions and methods for delivery to the central nervous system; in particular, the invention is directed to compositions and methods to reduce protein tyrosine phosphatase 1 B activity in the central nervous system.

BACKGROUND OF THE INVENTION The process of phosphorylation, defined as the attachment of a phosphate moiety to a biological molecule through the action of enzymes called kinases, represents one course by which intracellular signals are propagated resulting finally in a cellular response. Within the cell, proteins can be phosphorylated on serine, threonine or tyrosine residues and the extent of phosphorylation is regulated by the opposing action of phosphatases, which remove the phosphate moieties. While the majority of protein phosphorylation within the cell is on serine and threonine residues, tyrosine phosphorylation is modulated to the greatest extent during oncogenic transformation and growth factor stimulation (Zhang, (1998) Crit Rev. Biochem. MoI. Biol. 33:1-52). Because phosphorylation is such a ubiquitous process within cells and because cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disorders are a result of either aberrant activation of, or functional mutations in, kinases and phosphatases. Consequently, considerable attention has been devoted recently to the characterization of tyrosine kinases and tyrosine phosphatases.

Protein tyrosine phosphatase 1 B (PTP1 B) is an endoplasmic reticulum- associated enzyme originally isolated as the major protein tyrosine phosphatase of the human placenta (Tonks et al., (1988) J. Biol. Chem. 263:6731-6737; Tonks et al., (1988) J. Biol. Chem. 263:6722-6730).

A regulatory role in signaling mediated by the insulin receptor has been established for PTP1B. PTP1B interacts with and dephosphorylates the activated insulin receptor both in vitro and in intact cells resulting in the downregulation of the signaling pathway (Goldstein et al., (1998) MoI. Cell. Biochem. 182:91-99; Seely et al., (1996) Diabetes 45: 1379-1385). In addition, PTP1B modulates the mitogenic actions of insulin (Goldstein et al., (1998) MoI. Cell. Biochem. 182:91-99). In rat adipose cells overexpressing PTP1 B, the translocation of the GLUT4 glucose transporter was inhibited, implicating PTP1 B as a negative regulator of glucose transport as well (Chen et al., (1997) J. Biol. Chem. 272:8026-8031).

Mouse knockout models lacking the PTP1 B gene also point toward the negative regulation of insulin signaling by PTP1 B. Mice harboring a disrupted PTP1B gene showed increased insulin sensitivity, increased phosphorylation of the insulin receptor and when placed on a high-fat diet, PTP1B -/- mice were resistant to weight gain and remained insulin sensitive (Elchebly et al., (1999) Science (1999) 283:1544-1548).

PTP1 B, which is differentially regulated during the cell cycle (Schievella et al., (1993) Ce//. Growth Differ. 4:239-246), is expressed in insulin sensitive tissues as two different isoforms that arise from alternate splicing of the pre-mRNA (Shifrin and Neel, (1993) J. Biol. Chem. 268:25376-25384). It was recently demonstrated that the ratio of the alternatively spliced products is affected by growth factors such as insulin and differs in various tissues examined (Sell and Reese, (1999) MoI. Genet. Metab. 66:189-192). In these studies it was also found that the levels of the variants correlated with the plasma insulin concentration and percentage body fat and may therefore be used as a biomarker for patients with chronic hyperinsulinemia or type 2 diabetes.

Currently, therapeutic agents designed to inhibit the synthesis or action of PTP1B include small molecules (Ham et al., (1999) Bioorg. Med. Chem. Lett. 9: 185- 186; Skorey et al., (1997) J. Biol. Chem. 272:22472-22480; Taing et al., (1999)

Biochemistry 38:3793-3803; Taylor et al., (1998) Bioorg. Med. Chem. 6: 1457-1468; Wang et al., (1998) Bioorg. Med. Chem. Lett. 8:345-350; Wang et al., (1997) Biochem. Pharmacol. 54:703-711 ; Yao et al., (1998) Bioorg. Med. Chem. 6:1799- 1810) and peptides (Chen et al., (1999) Biochemistry 38:384-389; Desmarais et al., (1998) Arch. Biochem. Biophys. 354:225-231 ; Roller et al., (1998) Bioorg. Med. Chem. Lett. 8:2149-2150). In addition, disclosed in international patent publication WO 97/32595 are phosphopeptides and antibodies that inhibit the association of PTP1B with the activated insulin receptor for the treatment of disorders associated with insulin resistance. Antisense nucleotides against PTP1 B have also been disclosed (see e.g., Zinker et al., (2002) Proc. Nat. Acad. ScL 99:11357-11362; Rondinone et al., (2002) Diabetes 51 :2405-2411 ; U.S. Patent Publication Nos. 20030220282 and 20020055479 and U.S. Patent Nos. 6,261 ,840 and 6,602,857).

There remains a need in the art for improved compositions and methods for reducing PTP1 B activity. There is further a need in the art for compositions and methods for central treatment of metabolic diseases such as diabetes mellitus, metabolic syndrome and obesity as well as cancer and neurodegenerative diseases.

SUMMARY OF THE INVENTION

The present invention provides a method for administering compounds to the central nervous (CNS) system, for example, the brain or the hypothalamus (e.gr., mediobasal hypothalamus including the arcuate nucleus) to reduce protein tyrosine phosphatase (PTP1 B) activity therein. In particular embodiments, delivery to the CNS is achieved by intranasal or pulmonary delivery, thereby avoiding the need for invasive modes of administration directly to the CNS. In other representative embodiments, intranasal delivery is to the upper third of the nasal cavity, optionally the olfactory region and/or the sinus region. Accordingly, as a first aspect, the invention provides a pharmaceutical composition formulated for intranasal delivery to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region of the nose, or by pulmonary delivery to the lung, wherein the pharmaceutical composition comprises a compound that reduces protein tyrosine phosphatase 1 B (PTP1 B) activity in a pharmaceutically acceptable carrier. In general, the pharmaceutical compositions of the invention result in delivery of the compound that reduces PTP1 B activity to the CNS (for example, the brain or the hypothalamus [e.g., the ARC]).

The invention further provides a method of reducing PTP1B activity in the hypothalamus of a mammalian subject comprising intranasally administering to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region, of the mammalian subject an effective amount of a pharmaceutical composition * according to the invention.

Also provided is a method of treating diabetes mellitus in a mammalian _^ subject comprising intranasally administering to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region, of the mammalian subject an effective amount of a pharmaceutical composition according to the invention. „ As yet a further aspect, the invention provides a method of treating metabolic syndrome in a mammalian subject comprising intranasally administering to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region, of the mammalian subject an effective amount of a pharmaceutical composition according to the invention.

As yet another aspect, the invention provides a method of reducing peripheral glucose levels (e.g., in blood, plasma or serum) in a mammalian subject comprising intranasally administering to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region, of the mammalian subject an effective amount of a pharmaceutical composition according to the invention.

As another aspect, the invention provides a method of reducing glucose production in a mammalian subject comprising intranasally administering to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region, of the mammalian subject an effective amount of a pharmaceutical composition according to the invention.

In yet a further aspect, the invention provides a method of reducing food intake in a mammalian subject comprising intranasally administering to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region, of the mammalian subject an effective amount of a pharmaceutical composition according to the invention.

As another aspect, the invention provides a method of treating obesity in a mammalian subject comprising intranasally administering to the upper third of the nasal cavity, optionally the olfactory region and/or sinus region, of the mammalian subject an effective amount of a pharmaceutical composition according to the invention.

Still further, the invention provides a method of reducing PTP1 B activity in the hypothalamus of a mammalian subject comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to the invention. As another aspect, the invention provides a method of treating diabetes mellitus in a mammalian subject comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to the invention.

The invention further provides a method of treating metabolic syndrome in a mammalian subject comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to the invention. As yet another aspect, the invention provides a method of reducing peripheral glucose levels (e.g., in blood, plasma or serum) in a mammalian subject comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to the invention. Also provided is a method of reducing glucose production in a mammalian subject comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to the invention.

Also provided is a method of reducing food intake in a mammalian subject comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to the invention.

As yet another aspect, the invention provides a method of treating obesity in a mammalian subject comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to the invention. The invention further provides methods of identifying compounds for use in the methods of the invention.

Also provided is the use of a composition of the invention to reduce PTP1 B activity in the hypothalamus, treat diabetes, treat metabolic syndrome, reduce peripheral glucose levels (e.g., in blood, plasma or serum), reduce glucose production (e.g., by reducing gluconeogenesis), reduce lipid, triglyceride and/or cholesterol levels (e.g., in blood, plasma or serum), treat hyperglycemia, treat insulin resistance, treat glucose intolerance, treat leptin resistance, treat gonadotropin deficiency, treat heart failure, treat ischemia, treat atherosclerosis, treat coronary artery disease, treat hyperlipidemia, treat hypertriglyceridemia, treat hypercholesterolemia, treat familial lipoprotein lipase deficiency, treat hypertension, treat amenorrhea, treat polycystic ovary syndrome, treat cancer (including tumor forming cancers), treat neurodegenerative disease, reduce food intake, reduce appetite and/or treat obesity.

As yet another aspect, the invention provides methods of reducing PTP1 B activity in the hypothalamus, treating diabetes, treating metabolic syndrome, reducing peripheral glucose levels (e.g., in blood, plasma or serum), reducing glucose production (e.g., by reducing gluconeogenesis), reducing lipid, triglyceride and/or cholesterol levels (e.g., in blood, plasma or serum), treating hyperglycemia, treating insulin resistance, treating glucose intolerance, treating leptin resistance, treating gonadotropin deficiency, treating heart failure, treating ischemia, treating atherosclerosis, treating coronary artery disease, treating hyperlipidemia, treating hypertriglyceridemia, treating hypercholesterolemia, treating familial lipoprotein lipase deficiency, treating hypertension, treating amenorrhea, treating polycystic ovary syndrome, treating cancer (including tumor forming cancers), treating neurodegenerative disease, reducing food intake, reducing appetite and/or treating obesity by intranasal administration to the upper third of the nasal cavity, optionally the olfactory region and/or the sinus region, or by pulmonary administration to a subject of an effective amount of a compound of the invention.

The invention also provides intranasal and pulmonary delivery devices comprising one or more compounds (optionally, as a pharmaceutical composition) of the invention or a pharmaceutically acceptable salt or prodrug thereof.

The invention also provides a method of operating an intranasal delivery device comprising a compound that inhibits PTP 1 B activity (including pro-drugs and/or pharmaceutically acceptable salts). In representative embodiments, the invention provides a method of operating an intranasal delivery device comprising a pharmaceutical composition formulated for intranasal delivery, the pharmaceutical composition comprising a compound that inhibits PTP1 B activity in a pharmaceutically acceptable carrier. Optionally, the device is configured and/or operated and/or the composition is formulated to enhance delivery to the upper third of the nasal cavity, optionally the olfactory region and/or the sinus region of the nose.

In representative embodiments, the invention provides a method of operating an intranasal delivery device, the method comprising: activating the intranasal delivery device to deliver a compound that inhibits PTP1B activity

(including pro-drugs and/or pharmaceutically acceptable salts) to a target location so that the compound is delivered to the CNS. Optionally, the compound is delivered as part of a pharmaceutical composition formulated for intranasal delivery. Further, in particular embodiments, a therapeutically effective amount of the compound is delivered to the target location. Optionally, the device is configured and/or operated and/or the composition is formulated to enhance delivery to the upper third of the nasal cavity, optionally the olfactory region and/or the sinus region of the nose. According to this aspect of the invention, the activating step can further comprise positioning a unit dose container releasably holding the compound or pharmaceutical formulation; nebulizing or atomizing the agent in the device; and releasing the nebulized or atomized agent intranasally.

These and other aspects of the invention are set forth in more detail in the description of the invention below.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based, in part, on the discovery that compounds can be administered to the CNS, for example, the brain or the hypothalamus (e.g., the arcuate nucleus [ARC]) to reduce PTP1B activity resulting in reduced glucose production, reduced peripheral glucose levels and/or food intake, reduced lipid, triglyceride and/or cholesterol levels (e.g., in blood, plasma or serum), and/or to treat a metabolic disorder such as diabetes mellitus (e.g., type I or type II), metabolic syndrome, hyperglycemia, insulin resistance, glucose intolerance and/or obesity, and/or to treat disorders such as leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, amenorrhea, cancer (including tumor forming cancers), neurodegenerative disease, and/or polycystic ovary syndrome.

PTP1 B activity can be reduced by inhibiting enzymatic activity or by reducing the amount of enzymatically active PTP1 B protein at the transcriptional, post- transcriptional, translational and/or post-translational level. It should be understood that the amount of PTP1 B protein can be reduced by increasing the rate of degradation or removal of the protein and/or by decreasing the biosynthesis of the molecule. Accordingly, as used herein, "reducing PTP1B activity" (or grammatical equivalents and other like terms) encompasses inhibiting the enzyme activity of PTP1 B and/or decreasing the amount of enzymatically active PTP1 B protein by any suitable method. In particular embodiments, the compositions and methods of the present invention provide for the intranasal or pulmonary delivery of compounds to the CNS including the brain, for example, the hypothalamus (e.g., the ARC). In this regard and without being bound to any particular theory, it is believed that targeting the CNS by nasal administration is based on capture and internalization of substances by the olfactory receptor neurons, which substances are then transported inside the neuron to the olfactory bulb of the brain. Olfactory receptor neurons from the lateral olfactory tract within the olfactory bulb project to various regions such as the hippocampus, amygdala, thalamus, hypothalamus and other regions of the brain that are not directly involved in olfaction. These substances may also pass through junctions in the olfactory epithelium at the olfactory bulb and enter the subarachnoid space, which surrounds the brain, and the cerebral spinal fluid (CSF), which bathes the brain. Either pathway allows for targeted delivery without interference by the blood brain barrier, as neurons and the CSF, not the circulatory system, are involved in these transport mechanisms. Accordingly, intranasal delivery pathways permit compartmentalized delivery of compositions.

As further advantages, nasal delivery offers a noninvasive means of administration that is safe and convenient for self-medication. Further, intranasal administration can also provide for rapid onset of action due to ready absorption of the active agent across the nasal mucosa. These characteristics of nasal delivery result from several factors, including: (1) the nasal cavity has a relatively large surface area of about 150 cm² in man, (2) the submucosa of the lateral wall of the nasal cavity is richly supplied with vasculature, and (3) the nasal epithelium provides for a relatively high drug permeation capability due to thin single cellular layer absorption.

Pulmonary delivery (e.g., by inhalation) also offers a noninvasive means of administration that is safe and convenient for self-medication, and which also reduces the first-pass hepatic effect. As a result, pulmonary delivery can achieve greater bioavailability and lower therapeutic dosages. Pulmonary administration can also provide for rapid onset of action due to rapid and efficient absorption across the large surface monolayer (~100 m²) of the alveoli. Furthermore, deposition of the active agent in the lungs can provide a depot effect that results in greater therapeutic efficacy per dose and, in some embodiments, reduced dosage and/or frequency of administration.

As used herein administration by "inhalation" includes intranasal and pulmonary administration by the oral or nasal route, unless the context indicates that reference is only being made to intranasal or pulmonary administration. Delivery can be to any region(s) of the CNS. In particular embodiments, a compound or pharmaceutical composition is delivered to the spinal cord or to the brain, more specifically, the brainstem (medulla oblongata, pons), midbrain (hypothalamus, thalamus, epithalamus, pituitary gland, substantia nigra and/or pineal gland), cerebellum, telencephalon (corpus striatum, cerebrum [including the occipital, temporal, parietal and/or frontal lobes], cortex, basal ganglia [including the striatum, which further includes the caudate nucleus and/or the putamen], hippocampus and/or amygdala), limbic system, neocortex, corpus striatum, cerebrum, and/or inferior colliculus. The compound can further be delivered to different regions of the eye such as the retina, cornea and/or optic nerve. In particular embodiments, delivery is to the hypothalamus (e.g., the mediobasal hypothalamus such as the ARC).

As used herein, the terms "delivery to," "administration to" or "PTP1 B activity in" the hypothalamus (and similar terms) can refer to the hypothalamus when assessed as a whole, or can refer to particular regions of the hypothalamus (e.g., the mediobasal hypothalamus such as the ARC). The present invention will now be described with reference to the accompanying drawings, in which preferred embodiments of the invention are shown. This invention can be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. For example, features illustrated with respect to one embodiment can be incorporated into other embodiments, and features illustrated with respect to a particular embodiment can be deleted from that embodiment. In addition, numerous variations and additions to the embodiments suggested herein will be apparent to those skilled in the art in light of the instant disclosure, which do not depart from the instant invention.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference herein in their entirety.

As used in the description of the invention and the appended claims, the singular forms "a," "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

As used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ("or").

Applications of the Present Invention.

The present invention finds use in research as well as veterinary and medical applications. Suitable subjects include both avians and mammals. The term "avian" as used herein includes, but is not limited to, chickens, ducks, geese, quail, turkeys and pheasants. The term "mammal" as used herein includes, but is not limited to, humans, non-human primates, cattle, sheep, goats, pigs, horses, cats, dog, rabbits, rodents (e.g., rats and/or mice), etc. In particular embodiments, the subject is a human subject that has been diagnosed with or is considered at risk for a metabolic disorder such as diabetes mellitus (e.g., type I and/or type II), metabolic syndrome, hyperglycemia, insulin resistance, glucose intolerance and/or obesity. The subject can-further be a human subject that desires to lose weight for cosmetic and/or medical reasons. Alternatively, the subject can be a human subject that has been diagnosed with or is considered at risk for leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, amenorrhea, cancer (including tumor forming cancers), neurodegenerative disease, and/or polycystic ovary syndrome. Human subjects include neonates, infants, juveniles, and adults. In other embodiments, the subject used in the methods of the invention is an animal model of diabetes, hyperglycemia, metabolic syndrome, obesity, glucose intolerance, insulin resistance, leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, amenorrhea, cancer (including tumor forming cancers), neurodegenerative disease, and/or polycystic ovary syndrome. In particular embodiments of the invention, the subject is a subject "in need of the methods of the present invention, e.g., in need of the therapeutic effects of the inventive methods. For example, the subject can be a subject that has been diagnosed with or is considered at risk for diabetes mellitus (type I or type II), metabolic syndrome, hyperglycemia, insulin resistance, glucose intolerance, hyperphagia, obesity, leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, amenorrhea, cancer (including tumor forming cancers), neurodegenerative disease, and/or polycystic ovary syndrome, and the methods of the invention are practiced on the subject as a method of prophylactic and/or therapeutic treatment.

As one aspect, the invention provides a method of reducing PTP1 B activity in the CNS, for example, the brain or hypothalamus (e.g., mediobasal hypothalamus including the ARC) of a subject by intranasal or pulmonary administration to the subject of an effective amount of a compound or pharmaceutical composition that reduces PTP 1 B activity. Methods of determining PTP1B activity are known, for example, by assessing dephosphorylation of a phosphorylated insulin receptor substrate. In representative embodiments, PTP1B activity is reduced by at least about 25%, 40%, 50%, 60%, 75%, 80%, 85%, 90%, 95%, 97% or more as compared with a suitable control (e.g., the same subject prior to administration or another subject that has not been administered the compound or pharmaceutical composition that reduces PTP1 B activity).

In representative embodiments, the subject has a condition that is at least partially alleviated by a reduction in PTP1 B activity, including but not limited to obesity, type 2 diabetes, type 1 diabetes, hyperglycemia, insulin resistance, glucose intolerance, leptin resistance, metabolic syndrome, gonadotropin deficiency, amenorrhea, heart failure, ischemia, coronary heart disease, familial lipoprotein lipase deficiency, hypopituitarism, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, polycystic ovary syndrome, cancer (including tumor forming cancers), neurodegenerative disease, or any combination of the foregoing. The invention also provides a method of reducing glucose production in a subject by intranasal or pulmonary administration to the subject of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]). The term "glucose production" can refer to whole animal glucose production or glucose production by particular organs or tissues (e.g., the liver and/or skeletal muscle). Glucose production can be determined by any method known in the art, e.g., by the pancreatic/insulin clamp technique. In representative embodiments, glucose production is reduced by at least about 20%, 25%, 40%, 50%, 75% or more as compared with a suitable control. In particular embodiments, glucose production is normalized (e.g., as compared with a suitable healthy control) in the subject.

In representative embodiments, the subject has a condition that is at least partially alleviated by a reduction in glucose production, including but not limited to obesity, type 2 diabetes, type 1 diabetes, hyperglycemia, insulin resistance, glucose intolerance, leptin resistance, metabolic syndrome, gonadotropin deficiency, amenorrhea, heart failure, ischemia, coronary heart disease, familial lipoprotein lipase deficiency, hypopituitarism, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, polycystic ovary syndrome, cancer (including tumor forming cancers), neurodegenerative disease, or any combination of the foregoing.

The invention is also directed to methods of reducing peripheral glucose levels (e.g., in blood, plasma or serum) in a subject by intranasal or pulmonary administration of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity to a subject (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]). Peripheral glucose levels can be measured by any means known in the art, e.g., as described herein.

As used herein, "reducing peripheral blood glucose levels" and similar terms refer to a statistically significant reduction. The reduction can be, for example, at least about a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 75% reduction or more. In representative embodiments, the subject has a condition that is at least partially alleviated by a reduction in peripheral blood glucose levels, including but not limited to obesity, type 2 diabetes, type 1 diabetes, hyperglycemia, insulin resistance, glucose intolerance, leptin resistance, metabolic syndrome, gonadotropin deficiency, amenorrhea, heart failure, ischemia, coronary heart disease, familial lipoprotein lipase deficiency, hypopituitarism, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, polycystic ovary syndrome, cancer (including tumor forming cancers), neurodegenerative disease, or any combination of the foregoing. The invention further encompasses methods of treating diabetes (e.g., type-1 and/or type-2 diabetes), metabolic syndrome, hyperglycemia, insulin resistance and/or glucose intolerance in a subject by intranasal or pulmonary administration to the subject of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]).

As used herein, the term "diabetes" is used interchangeably with the term "diabetes mellitus." The terms "diabetes" and "diabetes mellitus" are intended to encompass both insulin dependent and non-insulin dependent (type I and type II, respectively) diabetes mellitus, unless one condition or the other is specifically indicated. Methods of diagnosing diabetes are well known in the art. In humans, diabetes is typically characterized as a fasting level of blood glucose greater than or equal to about 140 mg/dl or as a plasma glucose level greater than or equal to about 200 mg/dl as assessed at about two hours following the oral administration of a glucose load of about 75 g. "Metabolic syndrome" is characterized by a group of metabolic risk factors in one person, including one or more of the following: central obesity (excessive fat tissue in and around the abdomen), atherogenic dyslipidemia (blood fat disorders — mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls), raised blood pressure (e.g., 130/85 mmHg or higher), insulin resistance and/or glucose intolerance, a prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor in the blood), and proinflammatory state (e.g., elevated high-sensitivity C-reactive protein in the blood). As used herein, the presence of metabolic syndrome in a subject can be diagnosed by any method currently known or later developed in the art. The criteria proposed by the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) are the most widely used at this time to diagnose the metabolic syndrome. According to the ATP III criteria, the metabolic syndrome is identified by the presence of three or more of these components: central obesity as measured by waist circumference (men — greater than 40 inches; women — greater than 35 inches), fasting blood triglycerides greater than or equal to 150 mg/dL, blood HDL cholesterol (men — less than 40 mg/dl; women — less than 50 mg/dL), blood pressure greater than or equal to 130/85 mmHg, and fasting glucose greater than or equal to 110 mg/dL. The underlying causes of this syndrome are believed to be obesity, physical inactivity, and genetic factors. Subjects with metabolic syndrome are at increased risk of coronary heart disease, other diseases related to plaque buildup in artery walls (e.g., stroke and peripheral vascular disease) and/or type-2 diabetes. Metabolic syndrome has become increasingly common in the United States; as of October 2004, the American Heart Association estimates that about 47 million adults in the United States have metabolic syndrome.

Hyperglycemia is characterized by excessive blood (or plasma) glucose levels. Methods of diagnosing and evaluating hyperglycemia are known in the art. In general, fasting hyperglycemia is characterized by blood or plasma glucose concentration above the normal range after a subject has fasted for at least eight hours (e.g., the normal range is about 70-120 mg/dL). Postprandial hyperglycemia is generally characterized by blood or plasma glucose concentration above the normal range one to two hours after food intake by a subject.

By "insulin resistance" or "insulin insensitivity" it is meant a state in which a given level of insulin produces a less than normal biological effect (e.g., uptake of glucose). Insulin resistance is particularly prevalent in obese individuals or those with type-2 diabetes or metabolic syndrome. In type-2 diabetics, the pancreas is generally able to produce insulin, but there is an impairment in insulin action. As a result, hyperinsulinemia is commonly observed in insulin-resistant subjects. Insulin resistance is less common in type-l diabetics; although in some subjects, higher dosages of insulin have to be administered over time indicating the development of insulin resistance/insensitivity. The term "insulin resistance" or "insulin insensitivity" refers to whole animal insulin resistance/insensitivity unless specifically indicated otherwise (e.g., insulin resistance/insensitivity of a particular tissues(s) such as liver, skeletal muscle and/or adipose tissue). Methods of evaluating insulin resistance/insensitivity are known in the art, for example, hyperinsulinemic/ euglycemic clamp studies, insulin tolerance tests, uptake of labeled glucose and/or incorporation into glycogen in response to insulin stimulation, and measurement of known components of the insulin signaling pathway. "Glucose intolerance" is characterized by an impaired ability to maintain blood (or plasma) glucose concentrations following a glucose load (e.g., by ingestion or infusion) resulting in hyperglycemia. Glucose intolerance is generally indicative of an insulin deficiency or insulin resistance. Methods of evaluating glucose tolerance/intolerance are known in the art, e.g., the oral glucose tolerance test. As other aspects, the invention also encompasses methods of reducing appetite and/or food intake in a subject by intranasal or pulmonary administration to the subject of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]). As used herein, the term "food" is intended to encompass both food for human consumption and animal feed. In particular embodiments, intake of food is reduced by at least about 5%, 10%, 15%, 20%, 25%, 50%, 60%, 70% or even more as compared with a suitable control or the subject's previous eating pattern or behavior. Reductions in food intake can be determined by any method now known or later developed by those skilled in the art, for example, by a reduction in caloric intake and/or a reduction in the frequency of eating. Likewise, reduction in appetite can be determined by any method now known or later developed in the art, e.g., as a decrease in the subjective sensation of hunger and/or reduction in food intake (as defined above).

In representative embodiments, the subject has a condition that is at least partially alleviated by a reduction in appetite and/or food intake, including but not limited to obesity, type 2 diabetes, type 1 diabetes, hyperglycemia, insulin resistance, glucose intolerance, leptin resistance, metabolic syndrome, gonadotropin deficiency, amenorrhea, heart failure, ischemia, coronary heart disease, familial lipoprotein lipase deficiency, hypopituitarism, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, polycystic ovary syndrome, cancer (including tumor forming cancers), neurodegenerative disease, or any combination thereof. As another illustrative embodiment, the invention further provides a method of treating obesity in a subject by intranasal or pulmonary administration to the subject of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]). Any degree of obesity can be treated, and the inventive methods can be practiced for research, cosmetic and/or medical purposes. In particular embodiments, the subject is at least about 5%, 10%, 20%, 30%, 50, 75% or even 100% or greater over normal body weight. Methods of determining normal body weight are known in the art. For example, in humans, normal body weight can be defined as a BMI index of 18.5-24.9 kg/meter² (NHLBI (National Heart Lung and Blood institute) Obesity Education Initiative. The Practical Guide - Identification, Evaluation and Treatment of Overweight and Obesity in Adults. NIH Publication No. 00-4084 (2000); obtainable at http://www.nhlbi.nih.gov/quidelines/obesity/prctqd b.pdf). In particular embodiments, the invention is practiced to treat subjects having a BMI index of about 24.9 kg/meter² or greater. In exemplary embodiments, the methods of the invention result in at least about a 5%, 10%, 20%, 30%, 50% or greater reduction in degree of obesity (e.g., as determined by weight loss or by reduction in BMI).

In representative embodiments, the mammal has a condition that is at least partially alleviated by the treatment of obesity, including but not limited to type 2 diabetes, type 1 diabetes, hyperglycemia, insulin resistance, glucose intolerance, leptin resistance, metabolic syndrome, gonadotropin deficiency, amenorrhea, heart failure, ischemia, coronary heart disease, familial lipoprotein lipase deficiency, hypopituitarism, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, polycystic ovary syndrome, cancer (including tumor forming cancers), neurodegenerative disease, or any combination of the foregoing. Particular embodiments of the invention are directed to methods of reducing triglyceride levels (e.g., in blood, plasma or serum) in a mammal. The methods comprise intranasal or pulmonary administration of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity to the subject (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]). Triglyceride levels (e.g., in blood, plasma or serum) can be determined by any method known in the art.

In representative embodiments, triglyceride levels (e.g., in blood, plasma or serum) are reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 75% or more. In particular embodiments, triglyceride levels (e.g., in blood, plasma or serum) are normalized (e.g., as compared with a suitable healthy control) in the subject. Elevated and normal ranges of triglycerides can be readily determined. In particular embodiments, normal levels of serum triglycerides are in the range of 70-150 mg/dl.

In particular embodiments of this aspect of the invention, the subject has a condition that is at least partially alleviated by a reduction in triglyceride levels (e.g., in blood, plasma or serum), including but not limited to obesity, type 2 diabetes, type 1 diabetes, hyperglycemia, insulin resistance, glucose intolerance, leptin resistance, metabolic syndrome, insulin resistance, gonadotropin deficiency, amenorrhea, heart failure, ischemia, coronary heart disease, familial lipoprotein lipase deficiency, hypopituitarism, hyperlipidemia, hypertriglyceridemia, atherosclerosis, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, polycystic ovary syndrome, cancer (including tumor forming cancers), neurodegenerative disease, or any combination of the foregoing.

The invention also encompasses methods of treating cancer (including tumor forming cancers) in a mammal. The methods comprise intranasal or pulmonary administration of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity to the subject (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the spinal cord, the brain, the eye or the hypothalamus [e.g., the ARC]). Exemplary cancers include malignant disorders such as breast cancers; osteosarcomas, angiosarcomas, fibrosarcomas, soft tissue sarcomas, bone sarcomas and/or other sarcomas; leukemias; lymphomas; sinus tumors; ovarian, cervical, uterine, testicular, uretal, bladder, prostate and/or other genitourinary cancers; colon, esophageal and/or stomach cancers and/or other gastrointestinal cancers; lung cancers; myelomas; pancreatic cancers; liver cancers, kidney cancers; endocrine cancers; skin cancers; and/or central nervous system (e.g., spinal cord, brain and/or eye) and/or peripheral nervous system tumors, malignant and/or benign, including gliomas and/or neuroblastomas. Other cancers include without limitation B cell lymphoma, T cell lymphoma, myeloma, leukemia, hematopoietic neoplasias, thymoma, sarcoma, non-Hodgkins lymphoma, Hodgkins lymphoma, adenocarcinoma, renal cancer, primary or metastatic melanoma, squamous cell carcinoma, basal cell carcimona, head and neck carcinoma, thyroid carcinoma and any other cancer now known or later identified (see, e.g., Rosenberg (1996) Ann. Rev. Med. 47:481-491).

The invention also provides methods of treating a neurodegenerative disorder in a mammal. The methods comprise intranasal or pulmonary administration of an effective amount of a compound or pharmaceutical composition that reduces PTP1B activity to the subject (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the spinal cord, the brain, the eye or the hypothalamus [e.g., the ARC]). The invention can be practiced to treat any neurodegenerative disorder including but not limited to Huntington's disease, Alzheimer's disease, senile dementia, Pick's disease, Korsakov's syndrome, olivopontocerebellar degeneration, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Down's syndrome, Glutaric acidaemia, epilepsy, multi-infarct dementia, brain inflammation, spinal muscular atrophy, Friedrich's ataxia, Bassen-Kornzweig syndrome, Refsom's disease, retinal degeneration, Cruetzfelt-Jacob syndrome or prion disease (e.g., mad cow disease), dementia with Lewy bodies, schizophrenia, paraneoplastic cerebellar degeneration, and neurodegenerative conditions associated with stroke, AIDS, multiple sclerosis, peripheral sensory neuropathies and spinal cord injuries, and other neurodegenerative disorders characterized by impaired cognition. In representative embodiments, the neurodegenerative disorder is Alzheimer's disease.

In exemplary embodiments, the compound or pharmaceutical composition is delivered to the cerebellum (e.g., to treat Alzheimer's disease), to the hippocampus (e.g., to treat Alzheimer's disease or other disorders characterized by memory loss), to the basal ganglia (e.g., to treat Parkinson's disease) and/or or to the basal ganglia, striatal neurons and/or cortex (e.g., to treat Huntington's disease).

Clinical measures for assessing the efficacy of a treatment (therapeutic or prophylactic) for the various neurodegenerative disorders are known in the art, for example, diagnostic scales that assess a variety of clinical and functional parameters (e.g., Hazegawa's scale), computer tomography, positron emission tomography (PET), electroencephalogram (EEG), nuclear medicine techniques (e.g., SPECT), biomarkers, or functional tests (e.g., a water maze test and other memory-based tests), and the like.

The invention can also be practiced to treat leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypercholesterolemia (e.g., total serum cholesterol greater than 240 mg/dl and/or serum LDH greater than 130 mg/dl and, optionally, serum HDL less than 30 mg/dl), hypertension (e.g., systolic blood pressure greater than 140 and/or diastolic blood pressure less than 90), amenorrhea, polycystic ovary syndrome or any combination of the foregoing by intranasal or pulmonary administration of an effective amount of a compound or pharmaceutical composition that reduces PTP1 B activity to the subject (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]).

As used herein, an "effective amount" refers to an amount of a compound or pharmaceutical composition that is sufficient to produce a desired effect, which is optionally a therapeutic effect (i.e., by administration of a therapeutically effective amount). For example, an "effective amount" can be an amount that is sufficient to reduce PTP1 B activity, to reduce peripheral blood glucose levels, to reduce glucose production, to reduce appetite and/or food intake, to reduce lipid, triglyceride and/or cholesterol levels (e.g., in blood, plasma or serum), and/or to treat metabolic syndrome, hyperglycemia, glucose intolerance, insulin resistance, diabetes mellitus (e.g., type-2 or type-2 diabetes), obesity, leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, amenorrhea, cancer (including tumor forming cancers), neurodegenerative disease, and/or polycystic ovary syndrome. The foregoing methods can also be practiced by administering a compound that reduces PTP activity directly to the CNS or by peripheral administration and passage of the compound across the blood-brain barrier, each as described in more detail below.

A "therapeutically effective amount" or "amount effective to treat" (and similar terms) as used herein is an amount that provides some improvement or benefit to the subject. Alternatively stated, a "therapeutically effective amount" is an amount that provides some alleviation, mitigation and/or decrease in at least one clinical symptom. Clinical symptoms associated with the disorders that can be treated by the methods of the invention are well-known to those skilled in the art. Further, those skilled in the art will appreciate that the therapeutic effects need not be complete or curative, as long as some benefit is provided to the subject.

By the terms "treat," "treating" or "treatment of (or grammatically equivalent terms) it is meant that the severity of the subject's condition is reduced or at least partially improved or ameliorated and/or that some alleviation, mitigation or decrease in at least one clinical symptom is achieved and/or there is a delay in the progression of the condition and/or prevention or delay of the onset of a disease or illness. Thus, the terms "treat," "treating" or "treatment of (or grammatically equivalent terms) refer to both prophylactic and therapeutic treatment regimens.

By the terms "treating cancer" or "treatment of cancer" (and similar terms), it is intended that the severity of the cancer is reduced or the cancer is at least partially eliminated, and/or the incidence and/or onset of cancer is at least partially reduced or prevented, delayed, slowed, controlled and/or decreased in likelihood or probability, and/or that the spread of the cancer is slowed and/or reduced.

The present invention can also be used to screen or identify compounds that can be administered intranasally or to the lungs to reduce PTP1 B activity in the CNS, for example, the brain or hypothalamus (e.g., the ARC), to reduce peripheral glucose levels (e.g., in blood, plasma or serum), to reduce glucose production, to reduce appetite and/or food intake, reduce lipid, triglyceride and/or cholesterol levels (e.g., in blood, plasma or serum), and/or to treat metabolic syndrome, hyperglycemia, glucose intolerance, insulin resistance, diabetes mellitus (e.g., type-2 or type-2 diabetes), obesity, leptin resistance, gonadotropin deficiency, heart failure, ischemia, atherosclerosis, coronary artery disease, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, familial lipoprotein lipase deficiency, hypertension, amenorrhea, cancer (including tumor forming cancers), neurodegenerative disease, and/or polycystic ovary syndrome. Subjects for use in the screening methods of the invention are as described above. For example, in particular embodiments, a compound is administered intranasally or to the lungs of a subject and hypothalamic PTP1 B activity is evaluated. A reduction in PTP1 B activity in the CNS, for example, the brain or hypothalamus indicates that the compound is a compound that can be administered intranasally or to the lungs to reduce PTP1 B activity in the CNS, brain, or hypothalamus, respectively. Optionally, reduction in PTP1 B activity is evaluated by comparison with a suitable control.

As another non-limiting example, the invention provides a method of identifying a compound that can be administered intranasally or to the lungs to a subject to reduce glucose production, reduce peripheral glucose levels (e.g., in blood, plasma or serum) and/or to treat hyperglycemia, insulin resistance and/or glucose intolerance. In exemplary embodiments, a compound is administered intranasally or to the lungs of a subject and PTP1 B activity in the CNS₁ for example, the brain or hypothalamus (e.g., ARC) is determined. A reduction in PTP1B activity in the CNS, brain, or hypothalamus, respectively, indicates that the compound is a compound that can be administered intranasally or to the lungs to reduce glucose production, reduce peripheral glucose levels (e.g., in the blood, plasma or serum) and/or to treat hyperglycemia, insulin resistance and/or glucose intolerance. In particular embodiments, reduction in PTP1 B activity is evaluated by comparison with a suitable control. As a further non-limiting example, the invention provides a method of identifying a compound that can be administered intranasally or to the lungs of a subject to treat diabetes. In a representative embodiment, a compound is administered intranasally or to the lungs of a subject and PTP1 B activity in the CNS, for example, the brain or hypothalamus (e.g., ARC) is determined. A reduction in PTP1 B activity in the CNS, brain, or hypothalamus, respectively, indicates that the compound is a compound that can be administered intranasally or to the lungs to treat diabetes. Optionally, reduction in PTP1 B activity is evaluated by comparison with a suitable control.

The invention further provides a method of identifying a compound that can be administered intranasally or to the lungs of a subject to treat metabolic syndrome. In a representative embodiment, a compound is administered intranasally or to the lungs of a subject and PTP1 B activity in the CNS, for example, the brain or hypothalamus (e.g., ARC) is determined. A reduction in PTP 1 B activity in the CNS, brain or hypothalamus, respectively, indicates that the compound is a compound that can be administered intranasally or to the lungs to treat metabolic syndrome. Optionally, reduction in PTP1 B activity is evaluated by comparison with a suitable control.

The invention further encompasses methods of identifying a compound that can be delivered administered intranasally or to the lungs of a subject to reduce food intake and/or appetite. In a representative embodiment, a compound is administered intranasally or to the lungs of a subject and PTP1 B activity in the CNS, for example, the brain or hypothalamus (e.g., ARC) is determined. A reduction in PTP1B activity in the CNS, brain, hypothalamus, respectively, indicates that the compound is a compound that can be administered intranasally or to the lungs to reduce food intake and/or appetite. Optionally, reduction in PTP1 B is evaluated by comparison with a suitable control. In yet other representative embodiments, the methods of the invention are practiced to identify a compound that can be administered intranasally or to the lungs of a subject to treat obesity. In a representative embodiment, a compound is administered intranasally or to the lungs of a subject and PTP1 B activity in the CNS, for example, the brain or hypothalamus (e.g., ARC) is determined. A reduction in PTP1 B activity in the CNS, brain, hypothalamus, respectively, indicates that the compound is a compound that can be administered intranasally or to the lungs to treat obesity. Optionally, reduction in PTP1 B activity is evaluated by comparison with a suitable control.

In particular embodiments of the present invention, at least about 25%, 30%, 35%, 40%, 50%, 60%, 75% or more of the compound is delivered to the CNS rather than to peripheral tissues.

Compounds that Reduce PTPIB Activity in the CNS.

The compositions and methods of the invention can be practiced using any compound that can be administered to the CNS (e.g., by intranasal or pulmonary administration) to reduce PTP 1 B activity in the CNS, for example, the brain or hypothalamus (e.g., the ARC). Numerous compounds that reduce PTP1 B activity are known in the art. Other compounds can be identified by any method known in the art including but not limited to the methods disclosed in international patent publication WO 03/041729.

Examples of compounds that reduce PTP1B activity include small organic molecules, oligomers, polypeptides (including antibodies and antibody fragments), carbohydrates, lipids, coenzymes, nucleic acids (including DNA, RNA and chimerics and analogues thereof), nucleic acid mimetics, nucleotides, nucleotide analogs, as well as other molecules that directly or indirectly reduce PTP1 B activity. In particular embodiments, the compound is an inhibitory nucleic acid such as an interfering RNA (RNAi) including short interfering RNAs (siRNA), an antisense nucleic acid, a ribozyme or a nucleic acid mimetic.

As used herein, a "small organic molecule" is generally an organic molecule of less than about 2000 MW that is not an oligomer. Small non-oligomeric organic compounds include a wide variety of organic molecules, such as heterocyclics, aromatics, alicyclics, aliphatics and combinations thereof, comprising steroids, antibiotics, enzyme inhibitors, ligands, hormones, drugs, alkaloids, opioids, terpenes, porphyrins, toxins, catalysts, as well as combinations thereof.

Oligomers include oligopeptides, oligonucleotides, oligosaccharides, polylipids, polyesters, polyamides, polyurethanes, polyureas, polyethers, and poly (phosphorus derivatives), e.g. phosphates, phosphonates, phosphoramides, phosphonamides, phosphites, phosphinamides, etc., poly (sulfur derivatives) e.g., sulfones, sulfonates, sulfites, sulfonamides, sulfenamides, etc., where for the phosphorous and sulfur derivatives the indicated heteroatom is optionally bonded to C, H, N, O or S, and combinations thereof. In some embodiments, the compound is a PTP1B substrate analog. Further, the compound can be an inhibitor that binds to the ATP binding site, the active site (Ae., phosphotyrosine binding site) and/or a peripheral binding site. In particular embodiments, the compound is a bidentate inhibitor that binds to the active site and a peripheral binding site and inhibits PTP1 B activity (see, for example, as described by international patent publication WO 03/041729).

In particular embodiments, the compound is an antibody or antibody fragment that binds to PTP1B and reduces the activity thereof. The antibody or antibody fragment is not limited to any particular form and can be a polyclonal, monoclonal, bispecific, humanized, chimerized antibody or antibody fragment and can further be a Fab fragment, single chain antibody, and the like. Inhibitory anti-PTP1B antibodies have been described, see e.g., Zabolotny et al., (2001) Proc. Natl. Acad. ScL USA 98:5187-5192.

The nucleic acid sequences of PTP1B from a variety of species are known, which facilitates the synthesis of inhibitory oligonucleotides to reduce PTP1 B activity, see e.g., GenBank Accession No. NM_002827 (human PTP1B); GenBank Accession No. NM_011201 (mouse PTP1 B), and GenBank Accession No. NM_204875 (chicken PTP1B). A large number of compounds that reduce PTP1 B activity are known in the art. Examples of compounds that can be used in the compositions and methods of the invention to reduce PTP1 B activity include but are not limited to non-hydrolysable phosphotyrosine mimetic containing peptides; difluoromethylene phosphonates; 2- carbomethoxybenzoic acids; 2-oxalylaminobenzoic acids; lipophilic compounds; small molecule peptidomimetics (e.g., as described by Bleasdale et al., (2001) Biochemistry 40:5642-5654; Liljebris et al., (2002) J. Med. Chem. 45:1785-1798); 2,3,5-substituted biphenyls (e.g., as described by U.S. Patent Publication Nos. 2003/0083341 and 2004/0214869); phenyl oxo-acetic acids (e.g., as described by U.S. patent Publication No. 2004/0102480); substituted naphthoic acid derivatives (e.g., as described by U.S. Patent Publication No. 2004/0127570); 11-aryl- benzo[b]naphtha[2,3-d]furans and 11-aryl-benzo[b]naphtha[2,3-d]thiopenes (e.g., as described by Wrobel et al., (1999) J. Med. Chem. 42:3199-3202; Malamas et al.,

(2000) J. Med. Chem. 43:1293-1310); oxindole hydrazide derivatives (e.g., as described by U.S. Patent Publication No. 20050043388); substituted and unsubstituted benzooxathiazoles (e.g., 3H-benzo[1 ,2,3]oxathiazole 2,2-dioxides, 1 ,3- dihydrobenzo[1 ,2,5]thiadiazo-le 2,2,-dioxides and 1 ,3-dihydrobenzo[c]isothiazole 2,2- dioxides) and derivatives thereof; phosphonic acid biaryl derivatives (e.g., as described by U.S. Patent No. 6,486,141); inhibitory compounds containing two ortho- substituted aromatic phosphonates (e.g., as described by U.S. Patent Publication No. 2003/0114703 and Patent No. 6,448,429); phosphonic acid derivatives (e.g., as described by U.S. Patent Nos. 6,174,874 and 6,583,126); aryldifluoromethylphosphonic acids with sulfur containing substituents (e.g., as described by U.S. Patent Nos. 6,465,444 and 6,498,151); phosphonic and carboxylic acid derivatives (e.g., as described by U.S. Patent Nos. 6,365,592 and 6,486,142); neutral phosphotyrosine mimetics (e.g., as described by U.S. Patent Publication No. 20040009956); suramin derivatives (e.g., as described by McCain et al., (2004) J. Biol. Chem. 279:14713-14725); amino(oxo) acetic acid compounds (e.g., as described by U.S. Patent No. 6,627,767); and substituted methylene amide derivatives (e.g., as described by U.S. Patent Publication No. 20050124656); and pharmaceutically acceptable salts and prodrugs of the foregoing.

Other compounds that reduce PTP1 B activity are those described, for example, by Iversen et al., (2000) J. Biol. Chem. 275:10300-10307; Iversen et al.,

(2001) Biochemistry 40:14812-14820; Liu et al., (2002) Curr. Opin. Investig. Drugs 3:1608-1616; U.S. Patent No. 6,472,545; U.S. Patent No. 6,353,023; U.S. Patent No.

6,613,903; U.S. Patent No. 6,410,586; U.S. Patent No. 6,410,446; U.S. Patent No. 6,262,044; U.S. Patent No. 6,225,329; U.S. Patent No. 6,169,087; U.S. Patent No. 6,080,770; U.S. Patent No. 6,063,800; U.S. Patent No. 6,043,247; U.S. Patent No. 5,972,978; U.S. Patent No. 5,958,957; U.S. Patent No. 5,700,769; and U.S. Patent No. 6,225,329; and pharmaceutically acceptable salts and prodrugs of the foregoing.

For useful reviews of PTP1B inhibitors, see e.g., Pei et al., (2004) Current Pharmaceutical Design 10:3481-3504; Zhang et al., (2003) Expert Opin. Investig. Drugs 12:223-233; Zhang et al., (2002) Ann. Rev. Pharmacol. Toxicol. 42:209-234; Blaskovich et al., (2002) Expert Opin. Ther. Targets 12:871-905; Tobin et al., (2002) Curr. Opin. Drug. Discov. Devel. 5:500-512; Johnson et al., (2002) Nature Reviews (Drug Discovery) 1 :696-709; Moller et al., (2000) Curr. Opin. Drug Discov. Dev. 3:527-540; and Burke et al., (1998) Biopolymers (Peptide Science) 47:225-241.

In particular embodiments of the invention, the PTP1 B inhibitor is a 2- carboxyl, 3-carboxymethoxy, 5-aryl substituted thiophene as described in U.S. patent publication US 2005/0203087A1 (Wyeth Research) or is a pharmaceutically acceptable salt or prodrug thereof. In representative embodiments, the compound has the structure of formula (I):

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆. R₂ is R₅.

X is — O — C^alkylene-, — NR₈ — Ci-₃alkylene-, — S — Cr₃alkylene-, — SO — C_r3alkylene-, — SO₂- Ci-₃alkylene-, — C^alkylene-, — C₂-₄alkenylene-, or — C₂- ₄alkynylene-. Any of the alkylene, alkenylene or alkynylene groups can be optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q. Y is absent, ^O — , or — NR₆ — .

R₃ is H, halogen, CN, CF₃, OCF₃, Ci-₃alkyl, C_3-4cycloalkyl, C₁-_SaIkOXy, or aryl. R₄ is A-B-E-D, where A is absent or arylene, heteroarylene, C_1-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl. Each A can be optionally substituted with one or more of C_r6alkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q. Any of the alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q. Each A can be optionally terminated with one or more arylene, alkylene, or alkenylene. B is absent Or-NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-, -N(R₉)C(O)- -N(R₉)C(O)C(R₁₁)(R₁₂)-, -N(R₉)C(O)C(O)- - N(R₉)C(O)N(R₁₀)- — N(R₉)SO₂-; — N(R₉)SO₂C(R₁₀)(R₁₁)- — N(R₉)(Ri₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(Ri₄)- — 0— , — 0-C(R₁₁)(R₁₂), -0-C(Rn)(Ri₂)C(R₁₃)(R₁₄)- -C(R₁0(R₁₂J-O- -C(R₁₁)(R₁₂J-O- C(R₁₃)(R₁₄)-, -C(R₁₁)(R₁₂)N(R₉)-, -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)-, - C(R₁₁)(R₁₂)S-, -C(R_1I)(R₁₂)SC(R₁₃)(R₁₄)- Or-C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-.

E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Cr^alkylene, C₂-₁₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_halky!, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂.

D is one or more H, halogen, OH, NH₂, CHO, CN, NO₂, CF₃, or Q.

Each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, Or-S(O)_nR₇, and n is O, 1, or 2.

Each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-i₂cycloalkyl, Ci_-12alkoxyC_1-12alkyl, cycloalkylCr_δalkyl, 3- to 8-membered heterocycyl, heterocycylCrealkyl, aryl, arylC_r6alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl. Each R₅, R₆, and R₈ can be optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁, -NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂.

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆.

Each R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ is, independently, H, C^alkyl, C_2- i₂alkenyl, C_2-12alkynyl, C_3-i₂cycloalkyl, aryl, or aryld-^alkyl. Any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

The compound of the invention can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (I).

In representative embodiments, the PTP1B inhibitor is a compound of formula (I):

wherein R-i is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆.

R₂ is R₅.

X is — 0— Cr₃alkylene-, — NR₈ — Cr₃alkylene-, — S — Ci-₃alkylene-, —SO — Crsalkylene-, — SO₂ — Cr₃alkylene-, — C₁-₄alkylene-, — C₂-₄alkenylene-, or — C₂- ₄alkynylene-. Any of the alkylene, alkenylene or alkynylene groups can be optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q.

Y is absent, — O — , or — NR₆ — .

R₃ is H, halogen, CN, CF₃, OCF₃, Cr₃alkyl, C^cycloalkyl, Crsalkoxy, or aryl. R₄ is A-B-E-D, where A is absent or arylene, heteroarylene, C_1-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl. Each A can be optionally substituted with one or more of Cr₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q. Any of the alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q. Each A can be optionally terminated with one or more arylene, alkylene, or alkenylene.

B is absent or — NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-, -N(R₉)C(O)-, -N(R₉)C(O)C(R₁₁)(R₁₂)- -N(R₉)C(O)C(O)-, — N(R₉)C(O)N(R₁₀)-, -N(R₉)SO₂-, -N(R₉)SO₂C(R₁₀)(R₁₁)- - N(R₉)(Ri₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -O- -0-C(R₁₁)(R₁₂), -0-C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂J-O-, -C(R₁₁)(R₁₂J-O- C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)-, -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)- — C(R₁₁)(R₁₂)S-, -C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)-, Or-C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-.

E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Ci-)₂alkylene, C₂-₁₂alkenylene, or C₂-|₂alkynylene, where each E is optionally substituted with one or more C_1-3 alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂.

D is one or more H, halogen, OH, NH₂, CHO, CN, NO₂, CF₃, or Q.

When A, B, and E are absent, R₁ is C(O)OH or C(O)OCH₃, Rais H, and R₃ is H or chlorine, D is not H or chlorine; and when A, B, and E are absent, R₁ is C(O)OH or C(O)OCH₃, R₂ is H, and R₃ is H or bromine, D is not H or bromine. Each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, Or-S(O)_nR₇, and n is 0, 1, or 2.

Each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-12aikenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, C_1-12alkoxyC_1-12alkyl, cycloalkylC_r6aIkyl, 3- to 8-membered heterocycyl, heterocycylC_r6alkyl, aryl, arylC_r6 alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl. Each R₅, R₆, and R₈ can be optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁, -NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂. R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or —

S(O)₂NR₅R₆.

Each R₉, R-io, R₁₁, R₁₂, Ri₃ and Ri₄ is, independently, H, C_1-12alkyl, C_2- i₂alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl. Any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

In another representative embodiment, the PTP1B inhibitor is a compound of formula (I):

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆;

R₂ is R₅;

X is — O — Ci-₃alkylene-, — NR₈ — Crsalkylene-, — S — C^alkylene-, C^alkylene-, — SO₂ — C_r3alkylene-, — C^alkylene-, — C₂-₄alkenylene-, — C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q;

Y is absent, — O — , or— NR₆ — ;

R₃ is F, Br, I, CN, CF₃, OCF₃, Cr₃ alkyl, C_3-4cycloalkyl, C_r3alkoxy, or aryl; R₄ is A-B-E-D, where A is absent or arylene, heteroarylene, C_1-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl, each A being optionally substituted with one or more of C₁- ₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q; where any of the alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q; and each A being optionally terminated with one or more arylene, alkylene, or alkenylene;

B is absent or — NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-, -N(R₉)C(O)-, -N(R₉)C(O)C(R₁₁)(R₁₂)- -N(R₉)C(O)C(O)-, — N(R₉)C(O)N(R₁₀)- -N(R₉)SO₂-, -N(R₉)SO₂C(R₁₀)(R₁₁)- - N(R₉)(R₁₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)-, — O— , — 0-C(R₁₁)(R₁₂), -0-C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R^)-O-, -C(R₁₁)(R₁₂J-O- C(R₁₃)(Ri₄)- -C(R₁₁)(R₁₂)N(R₉)- -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)- - C(R₁₁)(R₁₂)S- , — C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)- or— C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-;

E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Cr^alkylene, C₂-₁₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_1-3 alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂;

D is one or more F, Cl, I, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, Or-S(O)_nR₇, where n is O, 1 , or 2; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-i₂alkenyl, C_2-12alkynyl,

C_3-12cycloalkyl, C_1-12alkoxyC_1-12alkyl, cycloalkylCrβalkyl, 3- to 8-membered heterocycyl, heterocycylCi-₆alkyl, aryl, arylC-i-e alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl, where each R₅, Re, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁, -NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂; and

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆; and each R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ is, independently, H, C_1-12alkyl, C_2-i₂alkenyl, C₂-₁₂alkynyl, C_3-12cycloalkyl, aryl, or arylCi_-12alkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

The compound of the invention can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (I). In a further representative embodiment, the PTP1B inhibitor is a compound of formula (I):

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆;

R₂ is R₅;

X is — 0 — Cr₃alkylene-, — NR₈ — Cr₃alkylene-, — S — Cr₃alkylene-, — SO — C_r3alkylene-, — SO₂- Crsalkylene-, — d-₄alkylene-, — C₂-₄alkenylene-, — C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q;

Y is absent, — O — , or — NR₆ — ; R₃ is F, Cl, I, CN, CF₃, OCF₃, Cp₃ alkyl, C₃^cycloalkyl, C,-₃alkoxy, or aryl;

R₄ is A-B-E-D, where A is absent or arylene, heteroarylene, C_1-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl, each A being optionally substituted with one or more of C₁- ₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q; where any of the alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q; and each A being optionally terminated with one or more arylene, alkylene, or alkenylene;

B is absent or— NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-, -N(R₉)C(O)- -N(R₉)C(O)C(R₁₁)(R₁₂)- -N(R₉)C(O)C(O)- - N(R₉)C(O)N(R₁₀)- -N(R₉)SO₂- -N(R₉)SO₂C(R₁₀)(R₁₁)- - N(R₉)(R₁₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- — O— , — 0-C(R₁₁)(R₁₂), -0-C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂J-O-, -C(R₁₁)(R₁₂J-O- C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)-, -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₄)-, - C(R₁₁)(R₁₂)S- , — C(R₁₁)(R₁₂)SC(R₁₃)(Ri₄)- , or— C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-;

E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, C_ri2alkylene, C₂-₁₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_1-3 alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂;

D is one or more F, Br, I, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, Or-S(O)_nR₇, where n is O, 1 , or 2; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-i₂alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, C_1-12alkoxyC_1-12alkyl, cycloalkylCrealkyl, 3- to 8-membered heterocycyl, heterocycylCVealkyl, aryl, arylC-pe alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl, where each R₅, R₆, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R_{1 I}, -NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂;

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆; and each R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ Js, independently, H, C_1-12alkyl, C_2-12alkenyl,

C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylCi_-12alkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

In other representative embodiments, the PTP1B inhibitor is a compound of formula (I):

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆; R₂Js R₅;

X is — O — C-i-₃alkylene-, — NR₈ — C_r3alkylene-, — S— Crsalkylene-, — SO — C_r3alkylene-, — SO₂ — Cr₃alkylene-, — C-i-₄alkylene-, — C₂-₄alkenylene-, — C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q;

Y is absent, — O — , or — N₆ — ;

R₃ is H, F, Cl, Br, I, CN, CF₃, OCF₃, C_r3 alkyl, C_3-4cycloalkyl, Cr₃alkoxy, or aryl;

R₄ is A-B-E-D, where A is absent or arylene, heteroarylene, C_1-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl, each A being optionally substituted with one or more of C₁- ₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q; where any of the alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q; and each A being optionally terminated with one or more arylene, alkylene, or alkenylene; B is absent or -NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-,

-N(R₉)C(O)- -N(R₉)C(O)C(R₁₁)(R₁₂)-, -N(R₉)C(O)C(O)-, — N(R₉)C(O)N(R₁₀)- -N(R₉)SO₂-, -N(R₉)SO₂C(R₁₀)(R₁₁)-, — N(R₉)(Ri₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- — O— , — 0-C(R₁₁)(R₁₂), -0-C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂J-O-, -C(R₁₁)(R₁₂J-O- C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)- -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)- —

C(R₁₁)(R₁₂)S- -C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)- or— C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-;

E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Cr₁₂alkylene, C₂-₁₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_1-3 alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂; D is one or more F, I, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆Rs, S(O)_nR₅, Or-S(O)_nR₇, where n is O, 1, or 2; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, C_1-2alkoxyC_1-12alkyl, cycloalkylCrealkyl, 3- to 8-membered heterocycyl, heterocycylCi~₆alkyl, aryl, arylCi-₆ alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl, where each R₅, R₆, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁, -NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂; R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or —

S(O)₂NR₅R₆; and each R₉, R₁₀, R₁₁, Ri₂, Ri₃ and R₁₄ is, independently, H, C,.i₂alkyl, C_2-i₂alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂;

In a further representative embodiment, the PTP1 B inhibitor is a compound of formula (I):

wherein Ri is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆;

R₂is R₅;

X is — O — C_r3alkylene-, — NR₈ — C_r3alkylene-, — S — Crsalkylene-, — SO — Crsalkylene-, — SO₂ — C-r₃alkylene-, — C_r4alkylene-, — C₂-₄alkenylene-, -C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q;

Y is absent, — O — , or — NR₆ — ; R₃is F, I, CN, CF₃, OCF₃, C_r3 alkyl, C^cycloalkyl, Crsalkoxy, or aryl;

B is absent Or -NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-, -N(R₉)C(O)- -N(R₉)C(O)C(R₁₁)(R₁₂)-, -N(R₉)C(O)C(O)-, — N(R₉)C(O)N(R₁₀)- -N(R₉)SO₂-, -N(R₉)SO₂C(R₁₀)(R₁₁)- - N(R₉)(R₁₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- — O— , -0-C(R₁₁)(R₁₂), -0-C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)-, -C(R₁₁)(R₁₂J-O-, -C(R₁₁)(R₁₂J-O- C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)-, -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)- - C(R₁₁)(R₁₂)S-, -C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)-, or— C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-;

E is absent or C₃-i₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Cr^alkylene, C₂-|₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_1-3 alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂;

D is one or more F, Cl, Br, I, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, Or-S(O)_nR₇, where n is O, 1 , or 2; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-12alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, C_1-12alkoxyC_1-12alkyl, cycloalkylC_r6alkyl, 3- to 8-membered heterocycyl, heterocycylC-realkyl, aryl, aryICrealkyl, arylC₂-₆ alkenyl, or arylC₂-6 alkynyl, where each R₅, R₆, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀Rn-NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂;

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₅, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆; and each R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄is, independently, H, C_1-12alkyl, C_2-12alkenyl,

C₂.₁₂alkynyl, C₃.₁₂cycloalkyl, aryl, or arylC-i_-12alkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂;

In representative embodiments of the invention, the compound of formula (I) as described in the preceding sections can include one or more of the following features:

R₁ can be C(O)OR₅ (e.g., C(O)OH, C(O)OCH₃, C(O)OCH₂CH₃, C(O)OCH₂CH₂CH₃, C(O)OCH(CH₃)CH₃, C(O)OCH₂CH(CH₃)CH₃, or benzyl ester).

R₁ can be C(O)NR₅R₆ (e.g., C(O)NH₂).

R₂ can be H, CH₃, CH₂CH₃, or CH(CH₃)CH₃.

X can be — O— C_1-3 alkylene- (e.g., — O— CH₂- , —O— CH(CH₃)- — O— CHF-). X can be -N-C_1-3 alkylene- (e.g., -N-CH₂-, — N-CHF-).

Y can be O.

R₃ can be H, halogen, CN, CF₃, OCF₃, Cr₃ alkyl, C_3-4cycloalkyl, or C_r3alkoxy. In certain embodiments, R₃ can be halogen, (e.g., fluorine, bromine, chlorine). In certain embodiments, R₃ can be H. In certain embodiments, R₃ can be C_1-3alkyl and can be optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q (e.g., CH₃, CF₃).

A, B, and E can be absent and D can be H.

A, B, and E can be absent and D can be halogen.

A can be a 6-membered aryl group and B-E-D can be connected to A in a meta (C-3 or C-5) position relative to the connection between A and thiophene.

A can be a 5-membered aryl group and B-E-D can be connected to A at the C-3 or C4 position relative to the connection between A and thiophene. A can be aryl optionally substituted with one or more C-realkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, Q, or B; where alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, Q, or B. A can be phenyl optionally substituted with one or more Cr₆alkyl, C₂-₆alkenyl,

C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, Q, or B; where alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, Q, or B.

A can be phenyl and is substituted with NR₅R₆ or NR₅R₇. A can be phenyl and is substituted with NR₅R₇, where R₇ is C(O)R₅, C(O)OR₅,

C(O)NR₅R₆, or S(O)₂R₅.

A can be phenyl.

A can be naphthyl.

A can be thiophene, indole, benzofuran, or pyridine. B can be -NR₇-, NR₅-, -NR₅CH₂-, NR₇CH₂-, —0—, — O—

C(R₁₁)(R₁₂)- or — C(R₁₁)(R₁₂J-O-.

B can be -NH-, -NHCH₂-, -NHC(O)CH₂-, -NHC(O)- — O— , — CH₂-O-, Or -O-CH₂-.

B can be -N(C(O)R₅)- -N(C(O)OR₅)- or — N(C(O)NHR₅)-. E can be cyclopentdiyl, cyclohexdiyl, cycloheptdiyl, piperidindiyl, piperazindiyl, pyrrolidindiyl, tetrahydrofurandiyl, morpholindiyl, phenylene, pyridindiyl, pyrimidindiyl, thiophendiyl, furandiyl, imidazoldiyl, pyrroldiyl, benzimidazoldiyl, tetrahydrothiopyrandiyl, or tetrahydropyrandiyl, where E is optionally substituted with one or more C_1-3alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂. E can be piperidindiyl optionally substituted with one or more C, ₃alkyl, C,

₃alkoxy, halogen, CN, OH, NH₂, or NO₂.

D can be -SO₂R₅, -C(O)R₅, -OC(O)NR₅R₆, -OR₅, -C(O)OR₅, pyrimidinyl or pyridinyl.

R₁ can be C(O)OH, X can be -OCH₂-, Y can be O, and R₂ can be H. R₁ can be C(O)OH, X can be -OCH₂-, Y can be O, R₂ can be H, and R₃ can be Br.

In certain embodiments, R₁ is C(O)OH, C(O)OCH₃, C(O)OCH₂CH₃, or C(O)NH₂. In other embodiments, R₂ is H, CH₃, CH₂CH₃, or t-butyl. In certain embodiments, X is — O— C_1-3alkyl~, -N-C_1-3 alkyl-, — S— C_1-3alkyl-, -SO-C_1- ₃alkyl-, or — SO₂- C_halky!-. In other embodiments, R₃ is H, F, Cl, Br, methyl, or CF₃.

In one embodiment, A is an aryl group substituted with B and may furthermore be optionally substituted with one or more of OH, NH₂, CHO, CN, NO₂, halogen, C₁-C₄ alkyl or Q; B can be absent or a 1-3 atom linker such as C₁-C₃ alkyl, C₂-C₃ alkenyl, NH, NHCO, NHCONH, NHSO₂, NHSO₂CH₂, NHCH₂, NHCH₂CH₂, O, OCH₂, OCH₂CH₂, CH₂O, CH₂OCH₂, CH₂NH, CH₂NHCH₂, CH₂S, CH₂SCH₂, or CH₂SO₂CH₂.

In the following examples, for the connection of B-E-D to A, it is shown that the meta positions (C-3 or C-5) relative to the connection between A and the thiophene ring are preferred when A is a 6-membered aryl group. When A is a 5- membered aryl group, the C-3 or C4 positions relative to the connection between A and the thiophene ring are preferred.

In another embodiment, E is absent or C₃-₈cycloalkylene, C₃-₈ heterocycdiyl, arylene, Cr₆alkylene, C₂-₆alkenylene, or C₂-₆alkynylene, and is optionally substituted with one or more C_1-3alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂. In certain embodiments, E can be cyclopentdiyl, cyclohexdiyl, cycloheptdiyl, piperidindiyl, piperazindiyl, pyrrolidindiyl, tetrahydrofurandiyl, morpholindiyl, phenylene, pyridindiyl, pyrimidindiyl, thiophendiyl, furandiyl, imidazoldiyl, pyrroldiyl, benzimidazoldiyl, tetrahydrothiopyrandiyl, or tetrahydropyrandiyl.

In one embodiment, D is one or more H, halogen, OH, NH₂, CHO, CN, NO₂, CF₃, aryl, or Q. In certain embodiments, D is SO₂R₇, -C(O)R₇, -OC(O)NR₅R₆, — OR₇, -COOR₇, -C(O)NR₅R₆, -C(O)R₇, pyrimidinyl or pyridinyl.

Specific and exemplary compounds of formula (I) are as described in United States patent publication US 2005/0203087 A1.

It should be recognized that a compound of formula (I) can contain chiral carbon atoms. In other words, it may have optical isomers or diastereoisomers.

One particular compound developed by Wyeth Research has the structure of formula (II):

(H)

The PTP1 B inhibitor can further be a pharmaceutically acceptable salt or prodrug of the compound of a compound of formula (II).

Compounds of formula (I) and (II) can be synthesized using art-known methods, e.g., as disclosed in U.S. patent publication US 2005/0203087 Al

In other embodiments, the PTP1B inhibitor can be a substituted bicyclic fused-thiophene as described in U.S. patent publication US 2005/0203081A1 (Wyeth Research) or is a pharmaceutically acceptable salt or prodrug thereof. In representative embodiments, the compound has the structure of formula (III): (III)

wherein R₁ is C(O)OR₇, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈. R₂ is C(O)ZR₄Or CN.

Z is — O— or -NR₅-.

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4aikylene-, — C_2-4alkenylene-, or — C_2- ₄alkynylene-. Any of the alkylene, alkenylene and alkynylene groups can be optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q.

Each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O. One or two of Yiι Y21 Y3. Y4. and Y₅ can be absent.

Each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q. Any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q.

Each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅.

Each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclic^- ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl. Each R₄, R₅, and R₆ can be optionally substituted with one or more C_1-6alkyl, C₂.₆alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈.

Each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl. Each R₇, R₈, and R₉ can be optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂. The compound of the invention can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (III).

In one representative embodiment, the PTP1B inhibitor is a compound of formula (III): (III)

R₁ is C(O)OR₇, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈.

R₂ is C(O)ZR₄Or CN. Z is — O— or — N R₅-.

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂- C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, or — C_2- ₄alkynylene-. Any of the alkylene, alkenylene and alkynylene groups can be optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q.

Each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O. One or two of Yi, Y2, Y3, Y₄, and Y₅ can be absent.

Each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q. Any of the aryl, heterocyclic, alky!, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q.

Each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-i₂alkenyl, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclic^. ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl. Each R₄, R₅, and R₆ can be optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈. Each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C₂-i₂alkenyl, C_2-i₂alkynyl, C^cycloalkyl, aryl, or arylC_1-12alkyl. Each R₇, R₈, and R₉ can be optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

When R₃ is H, the ring system is 1-benzothiophene, R₁ is C(O)OCH₃, and X is -OCH₂-, then R₂ is not C(O)OCH₃.

When R₃ is H, the ring system is 1-benzothiophene, R₁ is C(O)OH, and X is — OCH₂-, then R₂ is not C(O)OH.

When R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is — OCH₂ — , then R₂ is not C_1-3alkyl ester. When R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is C(O)OC_1-4alkyl, and X is -OCH₂- or — OCH(CH₃)- then R₂ is not CN.

When R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is -SCH₂CH₂-, then R₂ is not CN.

When R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is — SCH₂-, then R₂ is not isopropyl ester.

The compound of the invention can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (III).

In representative embodiments, the PTP1B inhibitor is a compound of formula (III): (III)

wherein R₁ is C(O)OR₇, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈;

R₂ Js C(O)ZR₄Or CN; Z is — O— or — N R₅-;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃, N, S, or O; where Y₅ is absent; each R₃ is, independently, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, —

C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylCi_-6aIkyl, 5- to 8-membered heterocycle, heterocyclicC^

₆alkyl, aryl, arylC^ealkyl, arylC₂.₆alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, or -S(O)₂NR₇R₈; each R₇, R₈, and Rg is, independently, H, Ci_-12alkyl, C_2-12alkenyl, C_1-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

In representative embodiments, this PTP1 B inhibitor is a compound of formula (III):

(III)

wherein R-i is C(O)OC_1-12alkyl, 5- to 6-membered heterocycle, H, halogen,

CN, or C(O)NR₇R₈;

R₂ is C(O)ZR₄ or CN, wherein R₄ is not methyl; Z is — O— or -NR₅-;

X is — O— C_1-3alkylene-, — NR₈- C_1-3alkylene-, — S— C_1-3alkylene-, — SO— C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C^alkylene-, — C^alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃; where Y₅ is absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -NR₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, Ci-i₆alkyl, C_2-12alkenyl, C_2-12alkynyl, C₃.₈cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC-j. ₆alkyl, aryl, arylC_1-6alkyl, arylC₂.₆alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C^alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₉R₉, — NR₇C(O)OR₉, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C^alkyl, C_2-i₂alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_2-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

In a further representative embodiment, the PTP1B inhibitor is a compound of formula (III):

(III)

wherein R₁ is C(O)OH, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈; R₂ is C(O)ZR₄ or CN, where R₄ is not H;

Z is — O— or -NR₅ X is — O — C_1-3alkylene-, -NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂- C,_-3alkylene-, — C^alkylene-, — C^alkenylene-, -C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃; where Y₅ is absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_halky!, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, —C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C₂.i₂alkynyl,

C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicd. ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-ealkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-2alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂. The compound of the invention can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (III).

In another representative embodiment, the PTP1 B inhibitor is a compound of formula (III):

(III)

wherein Ri is C(O)OH, C(O)OC_1-2alkyl, C(O)OC_4-12 alkyl, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈;

R₂ Js C(O)ZR₄;

Z is — O— or -NR₅-; X is — O — C_1-3alkylene-, — NR₈ — Ci_-3alkylene-, — S — C^alkylene-, — SO —

C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄ is, independently, CR₃, N, S, or O; where Y₅ is absent, and where at least one Y-i, Y₂, Y₃, and Y₄ is N; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NS(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, Ci_-16alkyl, C_2-12alkenyl, C_2-12alkynyl,

C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^ ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, Ci.i₂alkyl, C_1-12alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, aryl, or arylC-_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂. The compound of the invention can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (III).

In other representative embodiments, the PTP1B inhibitor is a compound of formula (III): (III)

wherein R₁ is C(O)OH, C(O)OC_5-12alkyl, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈; R₂ is C(O)ZR₄Or CN;

Z is — O— or -NR₅-;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂- C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, -C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, Y₄, and Y₅ Js, independently, CR₃, N, S, or O; where one or two of Y₁, Y₂, Y₃, Y₄, and Y₅ can be absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6aIkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^ ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, Ci_-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-i₂cycloalkyl, aryl, or arylC_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂. The compound of the invention can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (III).

In representative embodiments, the compounds of formula (III) as described in the preceding sections include one or more of the following features: R₁ can be C(O)OH.

R₁ can be C(O)OCH₃.

R₁ can be C(O)NH₂.

R₁ can be C(O)NHCH₃.

R₁ can be a 5-membered heterocycle.

X can be — O— C_1-3alkylene-(e.g., -OCH₂-, -OCHF-).

R₂ can be C(O)OH.

R₂ can be C(O)OCH₃.

R₂ can be C(O)OC_2-4alkane. X can be -OCH₂- and R₂ can be C(O)OH.

R₂ can be C(O)NH₂.

R₂ can be CN.

Y₅ can be absent and each Y₁, Y₂, Y₃, and Y₄ can be CR₃.

Y₅ can be absent and where one of Y₁, Y₂, Y₃, or Y₄ can be N, and the remaining Y₁, Y₂, Y₃, or Y₄ can each be CR₃.

X can be — OCH₂ — and Y₅ can be absent and each Y₁, Y₂, Y₃, and Y₄ can be CR₃.

X can be — OCH₂ — ; Y₅ can be absent and each Y₁, Y₂, Y₃, and Y₄ can be CR₃; R₁ can be C(O)OH; and R₂ can be C(O)OH. X can be — OCH₂ — , Y₅ can be absent, and where one of Y₁, Y₂, Y₃, or Y₄ can be N and the remaining Y₁, Y₂, Y₃, or Y₄ can each be CR₃.

X can be — OCH₂ — ; Y₅ can be absent, and where one of Y₁, Y₂, Y₃, or Y₄ can be N and the remaining Y₁, Y₂, Y₃, or Y₄ can each be CR₃; R₁ can be C(O)OH; and R₂ can be C(O)OH. R₃ can be a halogen.

R₃ can be an optionally substituted aryl.

In certain embodiments, R₁ is a 5- or 6-membered heterocycle. Nonlimiting examples of 5-membered heterocycles include the following:

In certain embodiments, Ri and R₂ are — C(O)OH or — C(O)OC_1-4alkyl. In another aspect, X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-

₃alkylene-, — SO C_1-3alkylene-, or — SO₂ — C_1-3alkylene-, wherein any alkylene group is optionally substituted with one or more F, Cl, CN, OCF₃, OH, NH₂, NO₂, CHO, or Q. In certain embodiments, X is — O — CH₂ — .

In another aspect, the fused heterocycle is benzothiophene or thienopyridine. Compounds of formula (III) can be synthesized using art-known methods, e.g., as described in U.S. patent publication US 2005/0203081A1.

Additional and exemplary compounds of formula (III) are as described in U.S. patent publication US 2005/0203081A1.

It should be recognized that a compound of formula (III) can contain chiral carbon atoms. In other words, it may have optical isomers or diastereoisomers.

The following terms are defined with respect to the compounds of formula (I), (II) and (III): "Alkyl" refers to hydrocarbon chains that can contain 1 to 10 (preferably 1 to 6; more preferably 1 to 4) carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, tert- butyl, isopentyl, neopentyl, octyl, or nonyl. "Alkenyl" refers to a straight or branched hydrocarbon chain containing one or more (preferably 1-4; more preferably 1-2) double bonds and can contain 2 to 10 carbon atoms. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, or 2-methyl-2-butenyl.

"Alkynyl" refers to a straight or branched hydrocarbon chain containing one or more (preferably 1 -4, or more preferably 1 -2) triple bonds and can contain 2 to 10 carbon atoms. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1~pentynyl, or 2-heptynyl.

"Cycloalkyl" refers to saturated or partly saturated monocyclic or polycyclic carbocyclic rings. Each ring can have from 3 to 10 carbon atoms. The term also can include a monocyclic or polycyclic ring fused to an aryl group or a heterocyclic group. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, or cyclopentenyl.

"Heterocyclyl", "heterocycle", or "heterocyclic" refers to a saturated or partially saturated monocyclic or polycyclic ring system containing at least one heteroatom selected from N, O and S (including SO and SO₂). Each of the rings can have from 3 to 10 atoms, except where defined otherwise. Examples of this definition include tetrahydrofuran, piperazine, piperidine, tetrahydropyran, morpholine, pyrrolidine, or tetrahydrothiophene.

The term "aryl" means monocyclic-, polycyclic, biaryl or heterocyclic aromatic rings. Each ring can contain 5 to 6 atoms. The term also may describe one of the foregoing aromatic rings fused to a cycloalkyl or heterocyclic group. "Heterocyclic aromatic" and "heteroaryl" means a monocyclic or polycyclic aromatic rings containing at least one heteroatom selected from N, O and S (including SO and SO₂) in the perimeter of the ring. Each ring can contain 5 to 6 atoms. Examples of aryl include phenyl, naphthyl, biphenyl, indanyl, indenyl, tetrahydronaphthyl, dihydrobenzopyranyl, fluorenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazoyl, thiadiazolyl, isothiazolyl, thienyl, thiophenyl, triazinyl, furanyl, pyridyl, tetrazolyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, 2,3- dihydrobenzofuranyl, benzothiophenyl, 2,3-dihydrobenzothiophenyl, furo(2,3- b)pyridyl, isoquinolyl, dibenzofuran, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, 4,5,6,7-tetrahydro-benzo[b]thiophenyl, indolyl, isoindolyl, 1 ,3-dihydro-isoindolyl, indazolyl, carbazolyl, 5H-dibenz[b,fJazepine, 10,11- dihydro-5H — dibenz[b,f]azepine, phenylpyridyl, phenylpyrimidinyl, phenylpyrazinyl, or phenypyridazinyl.

"Alkoxy" or alkyloxy" means an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. Examples include methoxy, ethoxy, or propyloxy. "Alkenyloxy" and "alkynyloxy" are similarly defined for alkenyl and alkynyl groups, respectively.

"Aryloxy" means an aryl group as defined above attached through an oxygen bridge. Examples include phenoxy or naphthyloxy. "Cycloalkyloxy" and "heterocyclyloxy" are similarly defined for cycloalkyl and heterocyclic groups, respectively.

Additional terms are similarly defined, following the convention that the last group in the term is the attachment point, unless is defined otherwise. For example, "arylalkenyl" represents an aryl group as defined above attached through an alkenyl group. A salt of any of the compounds of formula (I), (II) and (III) can be prepared.

For example, a pharmaceutically acceptable salt can be formed when an amino- containing compound of formula (I), (II) or (III) reacts with an inorganic or organic acid. Some examples of such an acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. Examples of pharmaceutically acceptable salts thus formed include sulfate, pyrosulfate bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, and maleate. A compound of formula (I), (II) or (III) may also form a pharmaceutically acceptable salt when a compound of formula (I), (II) or (III) having an acid moiety reacts with an inorganic or organic base. Such salts include those derived from inorganic or organic bases, e.g., alkali metal salts such as sodium, potassium, or lithium salts; alkaline earth metal salts such as calcium or magnesium salts; or ammonium salts or salts of organic bases such as morpholine, ethanol amine, choline, piperidine, pyridine, dimethylamine, or diethylamine salts.

The invention can also be practiced with pharmaceutical compositions comprising one or more compounds of formula (I), (II) and/or (III) or a pharmaceutically acceptable salt or prodrug thereof and a pharmaceutically acceptable carrier. Other compounds have been developed by Novo Nordisk, Abbott Laboratories, AstraZeneca, Novartis, Serono; Takeda, Pharmacia, Merck-Frosst, Sugen, as well as other pharmaceutical companies.

One particular compound of interest comprises a bidentate PTP1 B inhibitor as described by international patent publication WO 03/041729 and Shen et al.

(2001 , J. Biol. Chem. 276:47311-47319) as well as pharmaceutically acceptable salts or prodrugs thereof. The bidentate inhibitors comprise an active site-targeted component, a peripheral site-targeted component, and a linker component that joins the two. The inhibitor further comprises one or more nonhydrolyzable phosphate groups.

The active site-targeted component can be any appropriate compound, including non-hydrolyzable phosphotyrosine derivatives.

The linker component serves to provide a spacer and desirable charge characteristics between the active site and peripheral site components of the library members. As such, the linker is covalently bound to both the peripheral site-targeted and active site-targeted components, optionally by an amide bond. Suitable linkers include amino acids. The possible linkers can include a null member, wherein the peripheral site-targeted component is directly covalently bound to the active site- targeted component. Optionally, the linker component is less than 500 Dalton. In other embodiments, the linker component consists of carbon, oxygen, nitrogen, - and/or hydrogen. However, the use of other atomic elements is also possible.

The peripheral site-targeted component serves to target areas near the active site to increase specificity and affinity of the inhibitor interaction. Suitable peripheral site components include aryl groups covalently linked to non-hydrolyzable phosphate moieties. In particular embodiments, the peripheral site-targeted component consists of carbon, oxygen, nitrogen, sulfur, phosphorous and/or hydrogen. However, as with the linker component, the use of other atomic elements is also envisioned. The peripheral site component is also optionally less than about 500 Dalton.

In representative embodiments, the bidentate inhibitor has the structure of formula (IV): (IV)

wherein: A is defined as -H or-NHC(= O)(CH₂)_nH, where n = 1 to 18; and

B is defined as -H or -(CH₂)_nH, where n = 1 to 18.

In particular embodiments, A is -NHC(= O)(CH₂X₁H, where n = 12, 13 14, 15 and/or 16 and B is -H. In other particular embodiments, A is -H and B is -(CH₂)_nH, where n = 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 and/or 16. In representative embodiments, A is -NHC(= O)C₁₃H₂₇ and B is -H.

The compound can also be a pharmaceutically acceptable salt or prodrug of a compound of formula (IV).

It should be recognized that a compound of formula (IV) can contain chiral carbon atoms. In other words, it may have optical isomers or diastereoisomers. One particular compound of formula (IV), as described in international patent publication WO 03/041729, has the structure:

or is a pharmaceutically acceptable salt or prodrug thereof. The discussion herein is, for simplicity, provided without reference to stereoisomerism. However, the compounds of formula (I), (II), (III) and (IV) have one or more asymmetric carbon atoms. Thus, the structures of formula (I), (II), (III) and (IV) encompass both (i) the (R₁S) racemic mixtures of the compound, and (ii) single R or S enantiomeric forms of the compound. The resolution of racemates into enantiomeric forms can be performed by methods known in the art. For example, the racemate can be converted with an optically active reagent into a diasteriomeric pair, and the diasteriomeric pair subsequently separated into the enantiomeric forms.

Similarly, compounds of the invention containing a double bond can exist in the form of geometric isomers, which can be readily separated and recovered by conventional procedures. Such isomeric forms are included in the scope of this invention.

In other embodiments of the invention, the inhibitory compound comprises an inhibitory oligonucleotide, or a nucleic acid that encodes an inhibitory oligonucleotide, that specifically hybridizes to and reduces PTP1 B activity. By "specifically hybridize" (or grammatical variations) it is meant that there is a sufficient degree of complementarity or precise pairing between the inhibitory oligonucleotide and the target nucleic acid such that stable and specific binding occurs between the oligonucleotide and the target. It is understood in the art that the sequence of the inhibitory oligonucleotide need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable. An inhibitory oligonucleotide is specifically hybridizable when binding of the oligonucleotide to the target nucleic acid interferes with the normal function of the target nucleic acid (e.g., replication, transcription and/or translation), and there is a sufficient degree of complementarity to avoid non-specific binding of the inhibitory oligonucleotide to non-target nucleic acids under conditions in which specific binding is desired, e.g., under physiological conditions in the case of in vivo assays or therapeutic treatment and in the case of in vitro assays, under conditions in which the assays are performed. As is known in the art, a higher degree of sequence similarity is generally required for shorter oligonucleotides, whereas a greater degree of mismatched bases will be tolerated by longer oligonucleotides.

As discussed above, nucleic acid sequences encoding PTP1 B enzymes are known in the art and can be used to readily design inhibitory oligonucleotides against a target of interest. Inhibitory oligonucleotides, or nucleic acids encoding the same, can be administered using any suitable method for nucleic acid delivery. Methods for delivering nucleic acids to a subject or target cell are well known in the art. The inhibitory oligonucleotide or nucleic acid encoding the inhibitory oligonucleotide can be incorporated into a delivery vector for administration, e.g., a viral or non-viral vector, including liposomal vectors and plasmids. Suitable viral vectors include adeno-associated virus, lentivirus and adenovirus vectors. The nucleic acid or vector typically includes transcriptional and translational control elements such as promoters, enhancers and terminators.

In particular embodiments, the compound comprises a ribozyme (or a nucleic acid that encodes a ribozyme) that reduces PTP1B activity. Ribozymes are RNA- protein complexes that cleave nucleic acids in a site-specific fashion. Ribozymes have specific catalytic domains that possess endonuclease activity (Kim et al., (1987) Proc. Natl. Acad. Sci. USA 84:8788; Gerlach et al., (1987) Nature 328:802; Forster and Symons, (1987) Ce// 49:211). For example, a large number of ribozymes accelerate phosphoester transfer reactions with a high degree of specificity, often cleaving only one of several phosphoesters in an oligonucleotide substrate (Michel and Westhof, (1990) J. MoI. Biol. 216:585; Reinhold-Hurek and Shub, (1992) Nature 357:173). This specificity has been attributed to the requirement that the substrate bind via specific base-pairing interactions to the internal guide sequence ("IGS") of the ribozyme prior to chemical reaction.

Ribozyme catalysis has primarily been observed as part of sequence-specific cleavage/ligation reactions involving nucleic acids (Joyce, (1989) Nature 338:217). For example, U.S. Pat. No. 5,354,855 reports that certain ribozymes can act as endonucleases with a sequence specificity greater than that of known ribonucleases and approaching that of the DNA restriction enzymes. Thus, sequence-specific ribozyme-mediated inhibition of nucleic acid expression may be particularly suited to therapeutic applications (Scanlon et al., (1991) Proc. Natl. Acad. Sci. USA 88:10591 ; Sarver et al., (1990) Science 247:1222; Sioud et al., (1992) J. MoI. Biol. 223:831 ).

As another approach, the compound can comprise an antisense oligonucleotide or a nucleic acid encoding an antisense oligonucleotide that is directed against the coding sequence for a PTP1 B. The term "antisense oligonucleotide," as used herein, refers to a nucleic acid that is complementary to and specifically hybridizes to a specified DNA or RNA sequence. Antisense oligonucleotides and nucleic acids that encode the same can be made in accordance with conventional techniques. See, e.g., U.S. Patent No. 5,023,243 to Tullis; U.S. Patent No. 5,149,797 to Pederson et al.

Antisense oligonucleotides to PTP1 B have been described, for example, ISIS-113715 (see e.g., Zinker et al., (2002) Proc. Nat. Acad. Sci. 99:11357-11362; Rondinone et al., (2002) Diabetes 51 :2405-2411 ; U.S. Patent Publication Nos. 20030220282 and 20020055479 and U.S. Patent Nos. 6,261 ,840 and 6,602,857) as well as antisense constructs that target a Y-box protein binding site that functions as a transcription enhancer sequence in the promoter region situated upstream of the PTP1B gene (see, e.g., U.S. Patent Publication No. 20030223975).

Those skilled in the art will appreciate that it is not necessary that the antisense oligonucleotide be fully complementary to the target sequence as long as the degree of sequence similarity is sufficient for the antisense nucleotide sequence to specifically hybridize to its target (as defined above) and reduce production of the enzyme (e.g., by at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). To determine the specificity of hybridization, hybridization of such oligonucleotides to target sequences can be carried out under conditions of reduced stringency, medium stringency or even stringent conditions (e.g., conditions represented by a wash stringency of 35-40% Formamide with 5x Denhardt's solution, 0.5% SDS and 1x SSPE at 37⁰C; conditions represented by a wash stringency of 40- 45% Formamide with 5x Denhardt's solution, 0.5% SDS, and 1x SSPE at 42°C; and/or conditions represented by a wash stringency of 50% Formamide with 5x Denhardt's solution, 0.5% SDS and 1x SSPE at 42°C, respectively). See, e.g., Sambrook et al., Molecular Cloning, A Laboratory Manual (2d Ed. 1989) (Cold Spring Harbor Laboratory). Alternatively stated, in particular embodiments, antisense oligonucleotides of the invention have at least about 60%, 70%, 80%, 90%, 95%, 97%, 98% or higher sequence similarity with the complement of the target sequence and reduces enzyme production (as defined above). In some embodiments, the antisense sequence contains 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mismatches as compared with the target sequence.

As is known in the art, a number of different programs can be used to identify whether a nucleic acid or polypeptide has sequence similarity to a known sequence. Sequence similarity may be determined using standard techniques known in the art, including, but not limited to, the local sequence identity algorithm of Smith & Waterman, Adv. Appl. Math. 2, 482 (1981), by the sequence identity alignment algorithm of Needleman & Wunsch, J. MoI. Biol. 48,443 (1970), by the search for similarity method of Pearson & Lipman, Proc. Natl. Acad. ScL USA 85,2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wl), the Best Fit sequence program described by Devereux et al., Nucl. Acid Res. 12, 387-395 (1984), preferably using the default settings, or by inspection. Another example of a useful algorithm is the BLAST algorithm, described in Altschul et al., J. MoI. Biol. 215, 403-410, (1990) and Karlin et al., Proc. Natl. Acad. ScL USA 90, 5873-5787 (1993). A particularly useful BLAST program is the WU- BLAST-2 program which was obtained from Altschul et al., Methods in Enzymology, 266, 460-480 (1996); http://blast.wustl/edu/blast/ README.html. WU-BLAST-2 uses several search parameters, which are optionally set to the default values. The parameters are dynamic values and are established by the program itself depending upon the composition of the particular sequence and composition of the particular database against which the sequence of interest is being searched; however, the values may be adjusted to increase sensitivity.

An additional useful algorithm is gapped BLAST as reported by Altschul et al., (1997) Nucleic Acids Res. 25, 3389-3402.

The length of the antisense oligonucleotide is not critical as long as it specifically hybridizes to the intended target and reduces enzyme production (as defined above) and can be determined in accordance with routine procedures. In general, the antisense oligonucleotide is from about eight, ten or twelve nucleotides in length and/or less than about 20, 30, 40, 50, 60, 70, 80, 100 or 150 nucleotides in length.

An antisense oligonucleotide can be constructed using chemical synthesis and enzymatic ligation reactions by procedures known in the art. For example, an antisense oligonucleotide can be chemically synthesized using naturally occurring nucleotides or various modified nucleotides designed to increase the biological stability of the molecules and/or to increase the physical stability of the duplex formed between the antisense and sense nucleotide sequences, e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used.

Examples of modified nucleotides which can be used to generate the antisense oligonucleotide include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5- iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomet- hyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2- methylguanine, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5- methylaminomethyluracil, 5-methoxyaminornethyl-2-thiouracil, beta-D- mannosylqueosine, 5'-methoxycarboxyrhethyluracil, 5-methoxyuracil, 2-methylthio- N6-isopenten- yladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5- methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5- methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6- diaminopurine.

The antisense oligonucleotides of the invention further include nucleotide sequences wherein at least one, or all, or the internucleotide bridging phosphate residues are modified phosphates, such as methyl phosphonates, methyl phosphonothioates, phosphoromorpholidates, phosphoropiperazidates and phosphoramidates. For example, every other one of the internucleotide bridging phosphate residues can be modified as described.

As another non-limiting example, one or all of the nucleotides in the oligonucleotide can contain a 2' loweralkyl moiety (e.g., CrC₄, linear or branched, saturated or unsaturated alkyl, such as methyl, ethyl, ethenyl, propyl, 1-propenyl, 2- propenyl, and isopropyl). For example, every other one of the nucleotides can be modified as described. See also, Furdon et al., (1989) Nucleic Acids Res. 17, 9193- 9204; Agrawal et al., (1990) Proc. Natl. Acad. ScL USA 87, 1401-1405; Baker et al., (1990) Nucleic Acids Res. 18, 3537-3543; Sproat et al., (1989) Nucleic Acids Res. 17, 3373-3386; Walder and Walder, (1988) Proc. Natl. Acad. Sci. USA 85, 5011- 5015.

The antisense oligonucleotide can be chemically modified (e.g., at the 3' or 5' end) to be covalently conjugated to another molecule. To illustrate, the antisense oligonucleotide can be conjugated to a molecule that facilitates delivery to a cell of interest, enhances absorption by the nasal mucosa (e.g, by conjugation to a lipophilic moiety such as a fatty acid), provides a detectable marker, increases the bioavailability of the oligonucleotide, increases the stability of the oligonucleotide, improves the formulation or pharmacokinetic characteristics, and the like. Examples of conjugated molecules include but are not limited to cholesterol, lipids, polyamines, polyamides, polyesters, intercalators, reporter molecules, biotin, dyes, polyethylene glycol, human serum albumin, an enzyme, an antibody or antibody fragment, or a ligand for a cellular receptor.

Other modifications to nucleic acids to improve the stability, nuclease- resistance, bioavailability, formulation characteristics and/or pharmacokinetic properties are known in the art.

RNA interference (RNAi) provides another approach for reducing PTP1 B activity (e.g., shRNA or siRNA). According to this embodiment, the compound comprises an RNAi molecule, a nucleic acid that encodes an RNAi molecule, or a nucleic acid that can be processed to produce an RNAi molecule. RNAi is a mechanism of post-transcriptional gene silencing in which double-stranded RNA (dsRNA) corresponding to a target sequence of interest is introduced into a cell or an organism, resulting in degradation of the corresponding mRNA. The mechanism by which RNAi achieves gene silencing has been reviewed in Sharp et al, (2001) Genes Dei/ 15: 485-490; and Hammond et^'al., (2001) Nature Rev Gen 2: 110-119). The RNAi effect persists for multiple cell divisions before gene expression is regained. RNAi is therefore a powerful method for making targeted knockouts or "knockdowns" at the RNA level. RNAi has proven successful in human cells, including human embryonic kidney and HeLa cells (see, e.g., Elbashir et al., Nature (2001) 411:494-

8).

Initial attempts to use RNAi in mammalian cells resulted in antiviral defense mechanisms involving PKR in response to the dsRNA molecules (see, e.g., Gil et al. (2000) Apoptosis 5:107). It has since been demonstrated that short synthetic dsRNA of about 21 nucleotides, known as "short interfering RNAs" (siRNA) can mediate silencing in mammalian cells without triggering the antiviral response (see, e.g., Elbashir et al., Nature (2001) 411:494-8; Caplen et al., (2001) Proc. Nat. Acad. Sci. 98:9742). siRNA polynucleotides are known in the art for interfering with PTP1B expression (see, e.g., U.S. Patent Publication No. 20040009946).

In one embodiment, RNAi molecules (including siRNA molecules) can be expressed from nucleic acid expression vectors in vitro or in vivo as short hairpin RNAs (shRNA; see Paddison et al., (2002), PNAS USA 99:1443-1448), which are believed to be processed in the cell by the action of the RNase III like enzyme Dicer into 20-25mer siRNA molecules. The shRNAs generally have a stem-loop structure in which two inverted repeat sequences are separated by a short spacer sequence that loops out. There have been reports of shRNAs with loops ranging from 3 to 23 nucleotides in length. The loop sequence is generally not critical. Exemplary loop sequences include the following motifs: AUG, CCC, UUCG, CCACC, CTCGAG, AAGCUU, CCACACC and UUCAAGAGA.

The RNAi can further comprise a circular molecule comprising sense and antisense regions with two loop regions on either side to form a "dumbbell" shaped structure upon dsRNA formation between the sense and antisense regions. This molecule can be processed in vitro or in vivo to release the dsRNA portion, e.g., a siRNA.

International patent publication WO 01/77350 describes a vector for bidirectional transcription to generate both sense and antisense transcripts of a heterologous sequence in a eukaryotic cell. This technique can be employed to produce RNAi for use according to the invention. Shinagawa et al. (2003) Genes & Dev. 17:1340 reported a method of expressing long dsRNAs from a CMV promoter (a pol Il promoter), which method is also applicable to tissue specific pol Il promoters. Likewise, the approach of Xia et al., (2002) Nature Biotech. 20:1006, avoids poly(A) tailing and can be used in connection with tissue-specific promoters.

Methods of generating RNAi include chemical synthesis, in vitro transcription, digestion of long dsRNA by Dicer (in vitro or in vivo), expression in vivo from a delivery vector, and expression in vivo from a PCR-derived RNAi expression cassette (see, e.g., TechNotes 10(3) "Five Ways to Produce siRNAs," from Ambion, Inc., Austin TX; available at www.ambion.com).

Guidelines for designing siRNA molecules are available (see e.g., literature from Ambion, Inc., Austin TX; available at www.ambion.com). In particular embodiments, the siRNA sequence has about 30-50% G/C content. Further, long stretches of greater than four T or A residues are generally avoided if RNA polymerase III is used to transcribe the RNA. Online siRNA target finders are available, e.g., from Ambion, Inc. (www.ambion.com), through the Whitehead Institute of Biomedical Research (www.jura.wi.mit.edu) or from Dharmacon Research, Inc. (www.dharmacon.com/).

The antisense region of the RNAi molecule can be completely complementary to the target sequence, but need not be as long as it specifically hybridizes to the target sequence (as defined above) and reduces production of the target enzyme (e.g., by at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more). In some embodiments, hybridization of such oligonucleotides to target sequences can be carried out under conditions of reduced stringency, medium stringency or even stringent conditions, as defined above.

In other embodiments, the antisense region of the RNAi has at least about 60%, 70%, 80%, 90%, 95%, 97%, 98% or higher sequence similarity with the complement of the target sequence and reduces production of the target enzyme. In some embodiments, the antisense region contains 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 mismatches as compared with the target sequence. Mismatches are generally tolerated better at the ends of the dsRNA than in the center portion.

In particular embodiments, the RNAi is formed by intermolecular complexing between two separate sense and antisense molecules. The RNAi comprises a ds region formed by the intermolecular basepairing between the two separate strands. In other embodiments, the RNAi comprises a ds region formed by intramolecular basepairing within a single nucleic acid molecule comprising both sense and antisense regions, typically as an inverted repeat (e.g., a shRNA or other stem loop structure, or a circular RNAi molecule). The RNAi can further comprise a spacer region between the sense and antisense regions.

The RNAi molecule can contain modified sugars, nucleotides, backbone linkages and other modifications as described above for antisense oligonucleotides. Generally, RNAi molecules are highly selective. If desired, those skilled in the art can readily eliminate candidate RNAi that are likely to interfere with expression of nucleic acids other than the target by searching relevant databases to identify RNAi sequences that do not have substantial sequence homology with other known sequences, for example, using BLAST (available at www.ncbi.nlm.nih.gov/BLAST). Kits for the production of RNAi are commercially available, e.g., from New

England Biolabs, Inc. and Ambion, Inc.

A nucleic acid mimetic is an artificial compound that behaves similarly to a nucleic acid by having the ability to base-pair with a complementary nucleic acid.

Non-limiting examples of mimetics include peptide nucleic acids and phosphorothionate mimetics. Another example of a mimetic is an aptamer, which binds to and inhibits the target molecule in a manner similar to an antibody or small molecule inhibitor.

In embodiments of the invention, the compound is a reversible or irreversible inhibitor of PTP1 B enzymatic activity. Optionally, the compound is selective for inhibition of PTP1 B as compared with other PTPs or other phosphotyrosine binding proteins.

The compounds to be administered according to the present invention encompass pharmaceutically acceptable salts and prodrugs of the compounds described above. The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

Pharmaceutically acceptable base addition salts can be formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like.

Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al., (1977) "Pharmaceutical Salts," J. of

Pharma Sci. 66:1-19). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from the respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. As used herein, a "pharmaceutical addition salt" includes a pharmaceutically acceptable salt of an acid form of one of the components of the compositions of the invention. These include organic or inorganic acid salts of the amines.

Preferred acid salts are the hydrochlorides, acetates, salicylates, nitrates and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of a variety of inorganic and organic acids including, for example, with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic acids such as carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2- phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid; and with amino acids, such as naturally-occurring alpha-amino acids, for example glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2- disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2- sulfonic acid, naphthalene-1 ,5-disulfonic acid, 2- or 3-phosphoglycerate, glucose-6- phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates), or with other acid organic compounds, such as ascorbic acid. Pharmaceutically acceptable salts of compounds may also be prepared with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible. For oligonucleotides, preferred examples of pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, efc; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine and iodine.

The compounds of the invention can be pro-drugs that are converted to the active compound in vivo. For example, the compound can be modified to enhance cellular permeability (e.g., by esterification of polar groups) and then converted by cellular enzymes to produce the active agent. Methods of masking charged or reactive moieties as a pro-drug are known by those skilled in the art (see, e.g., P. Korgsgaard-Larsen and H. Bundgaard, A Textbook of Drug Design and Development, Reading U.K., Harwood Academic Publishers, 1991).

The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical

Association and Pergamon Press, 1987, both of which are incorporated by reference herein. See also US Patent No. 6,680,299. Exemplary prodrugs include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of the compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described, for example, in US Patent No. 6,680,324 and US Patent No. 6,680,322. The term "pharmaceutically acceptable prodrug" (and like terms) as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.

The compounds described above can further be modified to increase their lipophilicity and/or absorption across the blood-brain barrier, the nasal mucosa, or alveoli epithelium, e.g., by conjugation with lipophilic moieties such as fatty acids or by esterification.

The invention can be practiced with one or more PTP1B inhibitors, including but not limited to the PTP1B inhibitors specifically described herein. Methods of Administration to the CNS.

The blood-brain barrier presents a barrier to the passive diffusion of substances from the bloodstream into various regions of the CNS. However, active transport of certain agents is known to occur in either direction across the blood-brain barrier. Substances that may have limited access to the brain from the bloodstream can be injected directly into the cerebrospinal fluid. Cerebral ischemia and inflammation are also known to modify the blood-brain barrier and result in increased access to substances in the bloodstream. Administration of a therapeutic compound directly to the brain is known in the art. Intrathecal injection administers agents directly to the brain ventricles and the spinal fluid. Surgically-implantable infusion pumps are available to provide sustained administration of agents directly into the spinal fluid. Lumbar puncture with injection of a pharmaceutical compound into the cerebrospinal fluid ("spinal injection") is known in the art, and is suited for administration of compounds and compositions according to the present invention. In particular embodiments, intracerebroventricular (ICV) administration is used to deliver the compound (e.g., ICV injection through a surgically implanted cannulae). According to this embodiment, the ICV administration can be to the third cerebral ventricle of the brain. Thus, in representative embodiments, a compound that inhibits PTP1 B activity (including a pharmaceutically acceptable salts and/or prodrugs) can be administered directly to the brain of the mammal, e.g., by direct injection or through a pump.

Alternatively, the compound(s) can be administered peripherally in a manner that permits the compound to cross the blood-brain barrier of the mammal sufficiently to inhibit PTP1 B activity in the CNS. With any mode of administration, the compound can be formulated in a pharmaceutically acceptable excipient.

By "pharmaceutically acceptable" it is meant a material that (i) is compatible with the other ingredients of the composition without rendering the composition unsuitable for its intended purpose, and (ii) is suitable for use with subjects as provided herein without undue adverse side effects (such as toxicity, irritation, and allergic response). Side effects are "undue" when their risk outweighs the benefit provided by the composition. Non-limiting examples of pharmaceutically acceptable carriers include, without limitation, any of the standard pharmaceutical carriers such as phosphate buffered saline solutions, water, emulsions such as oil/water emulsions, microemulsions, and the like.

Further, the compound(s) can be formulated in a pharmaceutical composition that enhances the ability of the compound(s) to cross the blood-brain barrier of the mammal. Pharmacologic-based procedures are also known in the art for circumventing the blood brain barrier, including the conversion of hydrophilic compounds into lipid- soluble drugs. For example, the active compound can be encapsulated in a lipid vesicle or liposome. The intra-arterial infusion of hypertonic substances to transiently open the blood- brain barrier and allow passage of hydrophilic drugs into the brain is also known in the art. U.S. Patent No. 5,686,416 to Kozarich et al. discloses the co-administration of receptor mediated permeabilizer (RMP) peptides with therapeutic compounds to be delivered to the interstitial fluid compartment of the brain, to cause an increase in the permeability of the blood-brain barrier and effect increased delivery of the therapeutic compounds to the brain. Intravenous or intraperitoneal administration may also be used in practicing the present invention.

One method of transporting an active agent across the blood-brain barrier is to couple or conjugate the active compound to a second molecule (a "carrier"), which is a peptide or non-proteinaceous moiety selected for its ability to penetrate the blood-brain barrier and transport the active agent across the blood-brain barrier. Examples of suitable carriers include pyridinium, fatty acids, inositol, cholesterol, and glucose derivatives. The carrier may be a compound that enters the brain through a specific transport system in brain endothelial cells. Chimeric peptides adapted for delivering neuropharmaceutical agents into the brain by receptor-mediated transcytosis through the blood-brain barrier are disclosed in U.S. Patent No. 4,902,505 to Pardridge et al. These chimeric peptides comprise a pharmaceutical agent conjugated with a transportable peptide capable of crossing the blood-brain barrier by transcytosis. Specific transportable peptides disclosed by Pardridge et al. include histone, insulin, transferrin, and others. Conjugates of a compound with a carrier molecule, to cross the blood-brain barrier, are also disclosed in U.S. Patent No. 5,604,198 to Poduslo et al. Specific carrier molecules disclosed include hemoglobin, lysozyme, cytochrome c, ceruloplasmin, calmodulin, ubiquitin and substance P. See also U.S. Patent No. 5,017,566 to Bodor. The compound can be formulated without undue experimentation for administration to a mammal, including humans, as appropriate for the particular application. Additionally, proper dosages of the compositions can be determined without undue experimentation using standard dose-response protocols.

Accordingly, compositions designed for oral, lingual, sublingual, buccal and intrabuccal administration can be made without undue experimentation by means well known in the art, for example with an inert diluent or with an edible carrier. The compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the pharmaceutical compositions of the present invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. Tablets, pills, capsules, troches and the like may also contain binders, recipients, disintegrating agent, lubricants, sweetening agents, and flavoring agents. Some examples of binders include microcrystalline cellulose, gum tragacanth or gelatin. Examples of excipients include starch or lactose. Some examples of disintegrating agents include alginic acid, cornstarch and the like. Examples of lubricants include magnesium stearate or potassium stearate. An example of a glidant is colloidal silicon dioxide. Some examples of sweetening agents include sucrose, saccharin and the like. Examples of flavoring agents include peppermint, methyl salicylate, orange flavoring and the like. Materials used in preparing these various compositions should be pharmaceutically pure and nontoxic in the amounts used.

The compositions of the present invention can easily be administered parenterally such as for example, by intravenous, intramuscular, intrathecal or subcutaneous injection. Parenteral administration can be accomplished by incorporating the compositions of the present invention into a solution or suspension. Such solutions or suspensions may also include sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents. Parenteral formulations may also include antibacterial agents such as for example, benzyl alcohol or methyl parabens, antioxidants such as for example, ascorbic acid or sodium bisulfite and chelating agents such as EDTA. Buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose may also be added. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic.

Rectal administration includes administering the compound into the rectum or large intestine. This can be accomplished using suppositories or enemas.

Suppository formulations can easily be made by methods known in the art. For example, suppository formulations can be prepared by heating glycerin to about 120° C, dissolving the composition in the glycerin, mixing the heated glycerin after which purified water may be added, and pouring the hot mixture into a suppository mold. Transdermal administration includes percutaneous absorption of the composition through the skin. Transdermal formulations include patches (such as the well-known nicotine patch), ointments, creams, gels, salves and the like. Where the compound that inhibits PTP1 B activity is administered peripherally such that it crosses the blood-brain barrier, the compound can be formulated in a pharmaceutical composition that enhances the ability of the activator to cross the blood-brain barrier of the mammal. Such formulations are known in the art and include lipophilic compounds to promote absorption. Uptake of non-lipophilic compounds can be enhanced by combination with a lipophilic substance. Lipophilic substances that can enhance delivery of the compound across the nasal mucus include but are not limited to fatty acids (e.g., palmitic acid), gangliosides (e.g., GM-I), phospholipids (e.g., phosphatidylserine), and emulsifiers (e.g., polysorbate 80), bile salts such as sodium deoxycholate, and detergent-like substances including, for example, polysorbate 80 such as Tween™, octoxynol such as Triton™ X-100, and sodium tauro-24,25-dihydrofusidate (STDHF). See Lee et al., Biopharm., April 1988 issue:3037.

In particular embodiments of the invention, the compound is combined with micelles comprised of lipophilic substances. Such micelles can modify the permeability of the nasal membrane to enhance absorption of the compound. Suitable lipophilic micelles include without limitation gangliosides (e.g., GM-1 ganglioside), and phospholipids (e.g., phosphatidylserine). Bile salts and their derivatives and detergent-like substances can also be included in the micelle formulation. The active compound can be combined with one or several types of micelles, and can further be contained within the micelles or associated with their surface.

Alternatively, the active compound can be combined with liposomes (lipid vesicles) to enhance absorption. The active compound can be contained or dissolved within the liposome and/or associated with its surface. Suitable liposomes include phospholipids (e.g., phosphatidylserine) and/or gangliosides (e.g., GM-1). For methods to make phospholipid vesicles, see for example, U.S. Patent 4,921 ,706 to Roberts et al., and U.S. Patent 4,895,452 to Yioumas et al. Bile salts and their derivatives and detergent-like substances can also be included in the liposome formulation.

Other methods of delivering compounds across the blood-brain barrier are well- known in the art. Methods of intranasal and pulmonary administration to the CNS are discussed in more detail below.

Pharmaceutical Formulations and Methods for Intranasal Delivery.

The invention also encompasses pharmaceutical compositions formulated for intranasal administration comprising one or more compounds that reduce PTP1B activity (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]) in a pharmaceutically acceptable carrier. The one or more compounds can individually be a pharmaceutically acceptable salt and/or a prodrug that is converted to the active compound in vivo. Compounds that reduce PTP1B activity are discussed in more detail hereinabove.

The formulations of the invention can optionally comprise medicinal agents, pharmaceutical agents, carriers, dispersing agents, diluents, humectants, wetting agents, thickening agents, odorants, humectants, penetration enhancers, preservatives, and the like.

The compositions of the invention can be formulated for intranasal administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (20^th edition, 2000). Suitable nontoxic pharmaceutically acceptable nasal carriers will be apparent to those skilled in the art of nasal pharmaceutical formulations (see, e.g., Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton latest edition). Further, it will be understood by those skilled in the art that the choice of suitable carriers, absorption enhancers, humectants, adhesives, etc., will typically depend on the nature of the active compound and the particular nasal formulation, for example, a nasal solution (e.g., for use as drops, spray or aerosol), a nasal suspension, a nasal ointment, a nasal gel, or another nasal formulation. Aerosols are discussed in more detail in the following section.

The carrier can be a solid or a liquid, or both, and is optionally formulated with the composition as a unit-dose formulation. Such dosage forms can be powders, solutions, suspensions, emulsions and/or gels. With respect to solutions or suspensions, dosage forms can be comprised of micelles of lipophilic substances, liposomes (phospholipid vesicles/membranes), and/or a fatty acid (e.g., palmitic acid). In particular embodiments, the pharmaceutical composition is a solution or suspension that is capable of dissolving in the fluid secreted by mucous membranes of the olfactory epithelium, which can advantageously enhance absorption.

The pharmaceutical composition can be an aqueous solution, a nonaqueous solution or a combination of an aqueous and nonaqueous solution.

Suitable aqueous solutions include but are not limited to aqueous gels, aqueous suspensions, aqueous microsphere suspensions, aqueous microsphere dispersions, aqueous liposomal dispersions, aqueous micelles of liposomes, aqueous microemulsions, and any combination of the foregoing, or any other aqueous solution that can dissolve in the fluid secreted by the mucosal membranes of the nasal cavity. Exemplary nonaqueous solutions include but are not limited to nonaqueous gels, nonaqueous suspensions, nonaqueous microsphere suspensions, nonaqueous microsphere dispersions, nonaqueous liposomal dispersions, nonaqueous emulsions, nonaqueous microemulsions, and any combination of the foregoing, or any other nonaqueous solution that can dissolve or mix in the fluid secreted by the mucosal membranes of the nasal cavity.

Examples of powder formulations include without limitation simple powder mixtures, micronized powders, powder microspheres, coated powder microspheres, liposomal dispersions, and any combination of the foregoing. Powder microspheres can be formed from various polysaccharides and celluloses, which include without limitation starch, methylcellulose, xanthan gum, carboxymethylcellulose, hydroxypropyl cellulose, carbomer, alginate polyvinyl alcohol, acacia, chitosans, and any combination thereof.

In particular embodiments, the compound is one that is at least partially, or even substantially (e.g., at least 80%, 90%, 95% or more) soluble in the fluids that are secreted by the nasal mucosa (e.g., the mucosal membranes that surround the cilia of the olfactory receptor cells of the olfactory epithelium) so as to facilitate absorption. Alternatively or additionally, the compound can be formulated with a carrier and/or other substances that foster dissolution of the agent within nasal secretions, including without limitation fatty acids (e.g., palmitic acid), gangliosides (e.g., GM-I), phospholipids (e.g., phosphatidylserine, and emulsifiers (e.g., polysorbate 80).

Optionally, drug solubilizers can be included in the pharmaceutical composition to improve the solubility of the compound and/or to reduce the likelihood of disruption of nasal membranes which can be caused by application of other substances, for example, lipophilic odorants. Suitable solubilizers include but are not limited to amorphous mixtures of cyclodextrin derivatives such as hydroxypropylcylodextrins (see, for example, Pitha et al., (1988) Life Sciences 43:493-502). In representative embodiments, the compound is lipophilic to promote absorption. Uptake of non-lipophilic compounds can be enhanced by combination with a lipophilic substance. Lipophilic substances that can enhance delivery of the compound across the nasal mucus include but are not limited to esters, fatty acids (e.g., palmitic acid), gangliosides (e.g., GM-I), phospholipids (e.g., phosphatidylserine), and emulsifiers (e.g., polysorbate 80), bile salts such as sodium deoxycholate, and detergent-like substances including, for example, polysorbate 80 such as Tween™, octoxynol such as Triton™ X-100, and sodium tauro-24,25- dihydrofusidate (STDHF). See Lee et al., Biopharm., April 1988 issue:3037.

In particular embodiments of the invention, the active compound is combined with micelles comprised of lipophilic substances. Such micelles can modify the permeability of the nasal membrane to enhance absorption of the compound. Suitable lipophilic micelles include without limitation gangliosides (e.g., GM-1 ganglioside), and phospholipids (e.g., phosphatidylserine). Bile salts and their derivatives and detergent-like substances can also be included in the micelle formulation. The active compound can be combined with one or several types of micelles, and can further be contained within the micelles or associated with their surface.

Alternatively, the active compound can be combined with liposomes (lipid vesicles) to enhance absorption. The active compound can be contained or dissolved within the liposome and/or associated with its surface. Suitable liposomes include phospholipids (e.g., phosphatidylserine) and/or gangliosides (e.g., GM-1). For methods to make phospholipid vesicles, see for example, U.S. Patent 4,921 ,706 to Roberts et al., and U.S. Patent 4,895,452 to Yioumas et al. Bile salts and their derivatives and detergent-like substances can also be included in the liposome formulation. In representative embodiments, the pH of the pharmaceutical composition ranges from about 2, 3, 3.5 or 5 to about 7, 8 or 10. Exemplary pH ranges include without limitation from about 2 to 8, from about 3.5 to 7, and from about 5 to 7. Those skilled in the art will appreciate that because the volume of the pharmaceutical composition administered is generally small, nasal secretions may alter the pH of the administered dose, since the range of pH in the nasal cavity can be as wide as 5 to 8. Such alterations can affect the concentration of un-ionized drug available for absorption. Accordingly, in representative embodiments, the pharmaceutical composition further comprises a buffer to maintain or regulate pH in situ. Typical buffers include but are not limited to acetate, citrate, prolamine, carbonate and phosphate buffers.

In embodiments of the invention, the pH of the pharmaceutical composition is selected so that the internal environment of the nasal cavity after administration is acidic to neutral, which (1) can provide the active compound in an un-ionized form for absorption, (2) prevents growth of pathogenic bacteria in the nasal passage that is more likely to occur in an alkaline environment, and (3) reduces the likelihood of irritation of the nasal mucosa. Further, in particular embodiments, the net charge on the compound is a positive or neutral charge.

According to other embodiments of the invention, the compound has a molecular weight of about 50 kilodaltons or less, 10 kilodaltons or less, 5 kilodaltons or less, 2 kilodaltons or less, 1 kilodalton or less, or 500 daltons or less.

For liquid and powder sprays or aerosols, the pharmaceutical composition can be formulated to have any suitable and desired particle or droplet size. In illustrative embodiments, the majority and/or the mean size of the particles or droplets range in size from equal to or greater than about 1 , 2.5, 5, 10, 15 or 20 microns and/or equal to or less than about 25, 30, 40, 50, 60 or 75 microns (including all combinations of the foregoing). Representative examples of suitable ranges for the majority and/or mean particle or droplet size include, without limitation, from about 5 to 50 microns, from about 20 to 50 microns, from about 15 to 30 microns, and from about 10 to 15 microns, which facilitate the deposition of an effective amount of the active compound in the nasal cavity (e.g., in the olfactory region and/or in the sinus region). In general, particles or droplets smaller than about 5 microns will be deposited in the trachea or even the lung, whereas particles or droplets that are about 50 microns or larger generally do not reach the nasal cavity and are deposited in the anterior nose. International patent publication WO 2005/023335 (Kurve Technology, Inc.) describes particles and droplets having a diameter size suitable for the practice of representative embodiments of the present invention. For example, the particles or droplets can have a mean diameter of about 2 to 50 microns, about 5 to 50 microns, about 5 to 40 microns, about 5 to 35 microns, about 5 to 30 microns, about 5 to 20 microns, about 5 to 17 microns, about 5 to 30 microns, about 10 to 25 microns, about 10 to 15 microns, about 11 to 50 microns, about 11 to 30 microns, about 11 to 20 microns, about 11 to 15 microns, about 12 to 17 microns, about 15 to 25 microns, about 15 to 27 microns or about 17 to 23 microns.

In particular embodiments, the particles or droplets have a mean diameter of about 5 to 30 microns, about 10 to 20 microns, about 10 to 17 microns, about 10 to 15 microns, about 12 to 17 microns, about 10 to 15 microns or about 10 to 12 microns.

Further, the particles or droplets can have a mean diameter of about 10 to 20 microns, about 10 to 25 microns, about 10 to 30 microns, or about 15 to 30 microns. The particles can "substantially" have a mean diameter or size as described herein, i.e., at least about 50%, 60%, 70%, 80%, 90% or 95% or more of the particles are of the indicated diameter or size range. In representative embodiments of the invention, the composition is delivered as a nebulized liquid having a droplet size as described above.

In particular embodiments, the pharmaceutical composition is isotonic to slightly hypertonic, e.g., having an osmolarity ranging from about 150 to 550 mOsM. As another particular example, the pharmaceutical composition is isotonic having, e.g., an osmolarity ranging from approximately 150 to 350 mOsM.

According to particular methods of intranasal delivery, it can be desirable to prolong the residence time of the pharmaceutical composition in the nasal cavity (e.g., in the olfactory region and/or in the sinus region), for example, to enhance absorption. Thus, the pharmaceutical composition can optionally be formulated with a bioadhesive polymer, a gum (e.g., xanthan gum), chitosan (e.g., highly purified cationic polysaccharide), pectin (or any carbohydrate that thickens like a gel or emulsifies when applied to nasal mucosa), a microsphere (e.g., starch, albumin, dextran, cyclodextrin), gelatin, a liposome, carbamer, polyvinyl alcohol, alginate, acacia, chitosans and/or cellulose (e.g., methyl or propyl; hydroxyl or carboxy; carboxymethyl or hydroxylpropyl), which are agents that enhance residence time in the nasal cavity. As a further approach, increasing the viscosity of the dosage formulation can also provide a means of prolonging contact of agent with nasal epithelium. The pharmaceutical composition can be formulated as a nasal emulsion, ointment or gel, which offer advantages for local application because of their viscosity.

Moist and highly vascularized membranes can facilitate rapid absorption; consequently, the pharmaceutical composition can optionally comprise a humectant, particularly in the case of a gel-based composition so as to assure adequate intranasal moisture content. Examples of suitable humectants include but are not limited to glycerin or glycerol, mineral oil, vegetable oil, membrane conditioners, soothing agents, and/or sugar alcohols (e.g., xylitol, sorbitol; and/or mannitol). The concentration of the humectant in the pharmaceutical composition will vary depending upon the agent selected and the formulation. The pharmaceutical composition can also optionally include an absorption enhancer, such as an agent that inhibits enzyme activity, reduces mucous viscosity or elasticity, decreases mucociliary clearance effects, opens tight junctions, and/or solubilizes the active compound. Chemical enhancers are known in the art and include chelating agents (e.g., EDTA), fatty acids, bile acid salts, surfactants, and/or preservatives. Enhancers for penetration can be particularly useful when formulating compounds that exhibit poor membrane permeability, lack of lipophilicity, and/or are degraded by aminopeptidases. The concentration of the absorption enhancer in the pharmaceutical composition will vary depending upon the agent selected and the formulation.

To extend shelf life, preservatives can optionally be added to the pharmaceutical composition. Suitable preservatives include but are not limited to benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium chloride, and combinations of the foregoing. The concentration of the preservative will vary depending upon the preservative used, the compound being formulated, the formulation, and the like. In representative embodiments, the preservative is present in an amount of about 2% by weight or less. The pharmaceutical composition can optionally contain an odorant, e.g., as described in EP 0 504 263 B1 to provide a sensation of odor, to aid in inhalation of the composition so as to promote delivery to the olfactory region and/or to trigger transport by the olfactory neurons.

As another option, the composition can comprise a flavoring agent, e.g., to enhance the taste and/or acceptability of the composition to the subject.

The invention also encompasses methods of intranasal administration of the pharmaceutical formulations of the invention. In particular embodiments, the ^■ pharmaceutical composition is delivered to the upper third of the nasal cavity, optionally, in the olfactory region and/or the sinus region of the nose. The olfactory region is a small area that is typically about 2-10 cm² in man (25 cm² in the cat) located in the upper third of the nasal cavity for deposition and absorption by the olfactory epithelium and subsequent transport by olfactory receptor neurons. Located on the roof of the' nasal cavity, the olfactory region is desirable for delivery because it is the only known part of the body in which an extension of the CNS comes into contact with the environment (Bois et al., Fundamentals of Otolaryngology, p. 184, W.B. Saunders Co., PhNa., 1989).

In particular embodiments, the pharmaceutical composition is administered to the subject in an effective amount, optionally, a therapeutically effective amount (each as described hereinabove). Dosages of pharmaceutically active compositions can be determined by methods known in the art, see, e.g., Remington's

Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa; 18^th edition, 1990).

A therapeutically effective amount will vary with the age and general condition of the subject, the severity of the condition being treated, the particular compound or composition being administered, the duration of the treatment, the nature of any concurrent treatment, the carrier used, and like factors within the knowledge and expertise of those skilled in the art. As appropriate, a therapeutically effective amount in any individual case can be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation (see, e.g., Remington, The Science and Practice of Pharmacy (20^th ed. 2000)).

As a general proposition, a dosage from about 0.001, 0.01 or 0.1 to about 1, 2, 5, 10, 15, 20, 50, 75, 100, 200, 500 mg/kg body weight will have therapeutic efficacy, with all weights being calculated based upon the weight of the active ingredient, including salts. Dosages are typically determined based on age, surface area, weight, and condition of the subject. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219 (1966). Body surface area may be approximately determined from height and weight of the patient (see, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537 (1970)). Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient usage, and the possibility of co-usage, pre-treatment, or post-treatment, with other therapeutic treatments. In particular embodiments, the dosage is between about 0.1 and 10 mg/kg of the body weight, at least once a day and during the period of time, which is required to achieve the therapeutic effect. In other variations, the daily dose (or other dosage frequency) of an active compound is between about 0.1 and about 8 mg/kg body weight; or between about 0.1 to about 6 mg/kg body weight; or between about 0.1 and about 4 mg/kg body weight; or between about 0.1 and about 2 mg/kg body weight; or between about 0.1 and about 1 mg/kg body weight; or between about 0.5 and about 10 mg/kg body weight; or between about 1 and about 10 mg/kg body weight; or between about 2 and about 10 mg/kg body weight; or between about 4 to about 10 mg/kg body weight; or between about 6 to about 10 mg/kg body weight; or between about 8 to about 10 mg/kg body weight; or between about 0.1 and about 5 mg/kg body weight; or between about 0.1 and about 4 mg/kg body weight; or between about 0.5 and about 5 mg/kg body weight; or between about 1 and about 5 mg/kg body weight; or between about 1 and about 4 mg/kg body weight; or between about 2 and about 4 mg/kg body weight; or between about 1 and about 3 mg/kg body weight; or between about 1.5 and about 3 mg/kg body weight; or between about 2 and about 3 mg/kg body weight; or between about 0.01 and about 10 mg/kg; or between about 0.01 and 4 mg/kg; or between about 0.01 mg/kg and 2 mg/kg body weight; or between about 0.05 and 10 mg/kg body weight; or between about 0.05 and 8 mg/kg body weight; or between about 0.05 and 4 mg/kg body weight; or between about 0.05 and 4 mg/kg body weight; or between about 0.05 and about 3 mg/kg body weight; or between about 10 kg to about 50 kg body weight; or between about 10 to about 100 mg/kg body weight or between about 10 to about 250 mg/kg body weight; or between about 50 to about 100 mg/kg body weight or between about 50 and 200 mg/kg body weight; or between about 100 and about 200 mg/kg or between about 200 and about 500 mg/kg; or a dosage over about 100 mg/kg body weight; or a dosage over about 500 mg/kg body weight. The compound may be administered for a sustained period, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer.

Other dosing schedules may also be followed. For example, the frequency of the administration may vary. The dosing frequency can be a once weekly dosing. The dosing frequency can be a once daily dosing. The dosing frequency can be more than once weekly dosing. The dosing frequency can be more than once daily dosing, such as any one of 2, 3, 4, 5, or more than 5 daily doses. The dosing frequency can be 3 times a day. The dosing frequency can be three times a week dosing. The dosing frequency can be a four times a week dosing. The dosing frequency can be a two times a week dosing. The dosing frequency can be more than once weekly dosing but less than daily dosing. The dosing frequency can be a once monthly dosing. The dosing frequency can be a twice weekly dosing. The dosing frequency can be more than once monthly dosing but less than one weekly dosing. The dosing frequency can intermittent (e.g., one daily dosing for 7 days followed by no doses for 7 days, repeated for any 14 day time period, such as 2 months, 4 months, 6 months or more). The dosing frequency can be continuous (e.g., one weekly dosing for continuous weeks).

In other embodiments, the methods of the invention can be carried out on an as-needed by self-medication. Any of the dosing frequencies can be used with any dosage amount, for example, any of the dosing frequencies can employ a 10 mg/kg dosage amount. Any of the dosing frequencies can employ any of the compounds described herein together with any of the dosages described herein.

The pharmaceutical composition can be delivered in any suitable volume of administration. In representative embodiments of the invention, the administration volume for intranasal delivery ranges from about 25 microliters to 200 microliters or from about 50 to 150 microliters in a laboratory animal such as a rat or mouse and from about 50, 100, 250 or 500 microliters to about 1 , 2, 3, 3.5 or 4 milliliters in a human. Typically, the administration volume is selected to be small enough to allow for the dissolution of an effective amount of the active compound but sufficiently large to prevent therapeutically significant amounts of inhibitor from escaping from the anterior chamber of the nose and/or draining into the throat, post nasally. Any suitable method of intranasal delivery can be employed for delivery of the pharmaceutical compound. In particular embodiments, intranasal administration is by inhalation (e.g., using an inhaler, atomizer or nebulizer device), alternatively, by spray, tube, catheter, syringe, dropper, packtail, pledget, and the like. As a further illustration, the pharmaceutical composition can be administered intranasally as (1) nose drops, (2) powder or liquid sprays or aerosols, (3) liquids or semisolids by syringe, (4) liquids or semisolids by swab, pledget or other similar means of application, (5) a gel, cream or ointment, (6) an infusion, or (7) by injection, or by any means now known or later developed in the art. In particular embodiments, the method of delivery is by nasal drops, spray or aerosol. As used herein, aerosols can be used to deliver powders, liquids or dispersions (solids in liquid).

In representative embodiments, the pharmaceutical formulation is directed upward during administration, so as to enhance delivery to the upper third (e.g., the olfactory epithelium in the olfactory region) and the side walls (e.g., nasal epithelium) of the nasal cavity. Further, orienting the subject's head in a tipped-back position or orienting the subject's body in Mygind's position or the praying-to-Mecca position can be used to facilitate delivery to the olfactory region.

Many devices are known in the art for nasal delivery. Exemplary devices include particle dispersion devices, bidirectional devices, and devices that use chip- based ink-jet technologies. ViaNase (Kurve Technolgies, Inc., USA) uses controlled particle dispersion technology (e.g., an integrated nebulizer and particle dispersion chamber apparatus, for example, as described in International patent publication WO 2005/023335). Optinose and Optimist (OptiNose, AS, Norway) and DirectHaler (Direct-Haler A/S, Denmark) are examples of bidirectional nasal delivery devices. Ink-jet dispensers are described in U.S. Patent No. 6,325,475 (MicroFab

Technologies, Inc., USA) and use microdrops of drugs on a millimeter sized chip. Devices that rely on iontophoresis/phonophoresis/electrotransport are also known, as described in U.S. Patent No. 6,410,046 (Intrabrain International NV, Curacao, AN). These devices comprise an electrode with an attached drug reservoir that is inserted into the nose. Iontophoresis, electrotransport or phonophoresis with or without chemical permeation enhancers can be used to deliver the drug to the target region (e.g., olfactory).

Nasal delivery devices are also described in U.S. Patent No. 6,715,485 (OptiNose AS); U.S. Patent No. 6,325,475 (Microfab Technologies, Inc.); U.S. Patent No. 6,948,492 (University of Kentucky Research Foundation); U.S. Patent No.

6,244,573 (LyteSyde, LLC); U.S. Patent No. 6,234,459 (LyteSyde, LLC); U.S. Patent No. 6,244,573 (LyteSyde, LLC); U.S. Patent No. 6,113,078 (LyteSyde, LLC); U.S. Patent No. 6,669,176 (LyteSyde, LLC); U.S. Patent No. 5,724,965 (Respironics Inc.); and U.S. Patent Publications US2004/0112378 A1 ; US 2004/0112379 A1; US 2004/0149289 A1 ; US 2004/0112380 A1 ; US 2004;0182388 A1 ; US 2005/0028812 A1; US 2005/0235992 A1 ; US 2005/0072430 A1 and US 2005/0061324 A1. Further, the pharmaceutical compositions of the present invention can optionally be administered in conjunction with other therapeutic agents, for example, other therapeutic agents useful in the treatment of hyperglycemia, diabetes, metabolic syndrome, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, hypertension, atherosclerosis, ischemia, heart failure, coronary artery disease and/or obesity. For example, the compounds of the invention can be administered in conjunction with insulin therapy and/or hypoglycemic agents (e.g., metformin). The additional therapeutic agent(s) can optionally be administered concurrently with the compounds of the invention, in the same or different formulations. As used herein, the word "concurrently" means sufficiently close in time to produce a combined effect (that is, concurrently can be simultaneously, or it can be two or more events occurring within a short time period before or after each other).

The invention also provides a method of operating an intranasal delivery device comprising a compound that inhibits PTP1B activity (including pro-drugs and/or pharmaceutically acceptable salts thereof). In representative embodiments, the invention provides a method of operating an intranasal delivery device comprising a pharmaceutical composition formulated for intranasal delivery, the pharmaceutical composition comprising a compound that inhibits PTP1 B activity in a pharmaceutically acceptable carrier. Optionally, the device is configured and/or operated and/or the composition is formulated to enhance delivery to the upper third of the nasal cavity, optionally the olfactory region and/or the sinus region of the nose. In representative embodiments, the invention provides a method of operating an intranasal delivery device, the method comprising: activating the intranasal delivery device to deliver a compound that inhibits PTP1 B activity (including pro-drugs and/or pharmaceutically acceptable salts) to a target location so that the compound is delivered to the CNS. Optionally, the compound is delivered as part of a pharmaceutical composition formulated for intranasal delivery. Further, in particular embodiments, a therapeutically effective amount of the compound is delivered to the target location. Optionally, the device is configured and/or operated and/or the composition is formulated to enhance delivery to the upper third of the nasal cavity, optionally the olfactory region and/or the sinus region of the nose.

According to this aspect of the invention, the activating step can further comprise positioning a unit dose container releasably holding the compound or pharmaceutical formulation; nebulizing or atomizing the agent in the device; and releasing the nebulized or atomized agent intranasally.

The invention also encompasses an intranasal delivery device comprising one or more compounds of the invention (optionally as a pharmaceutical composition as described herein).

Pharmaceutical Formulations and Methods for Pulmonary Delivery.

The invention also provides pharmaceutical compositions formulated for pulmonary administration comprising one or more compounds that reduce PTP1B activity (e.g., to deliver the compound or pharmaceutical composition to the CNS, for example, the brain or the hypothalamus [e.g., the ARC]) in a pharmaceutically acceptable carrier (as described above). Compounds that can be used in the pharmaceutical compositions of the invention are discussed herein and include prodrugs and/or pharmaceutically acceptable salts. "Pulmonary administration" or "administration to the lungs," and like terms, are used interchangeably herein. These terms refer to delivery of a composition to the lung(s) of a subject, e.g., the bronchi, bronchioli and/or alveoli. Generally, pharmaceutical compositions administered to the respiratory tract by oral or nasal inhalation travel through the upper airways (oropharynx and larynx), the lower airways which include the trachea followed by bifurcations into the bronchi and bronchioli and through the terminal bronchioli which in turn divide into respiratory bronchioli leading then to the ultimate respiratory zone, the alveoli or the deep lung. Absorption through the alveoli results from rapid dissolution of the formulation in the ultra-thin (0.1 μm) fluid layer of the alveolar lining of the lung. According to certain aspects of the invention, pulmonary administration is to the deep lung or alveoli. In particular embodiments of the invention, at least about 5%, 10%, 20%, 30%, 40%, 50% or more of the mass of particles deposits in the deep lung or alveoli. Deposition in the deep lung, for example the alveoli, can be influenced by a variety of factors including the delivery method, the characteristics of the delivery device (e.g., the size of the particles produced, the delivery velocity, and the like), and the characteristics of the delivered composition. Compositions and methods for achieving enhanced delivery to the deep lung or alveoli are discussed below.

In particular embodiments, the pharmaceutical composition is administered to the subject in an effective amount, optionally, a therapeutically effective amount (each as described herein). As a general proposition, a dosage from about 0.1 to about 5, 10, 20, 50, 75 or 100 mg active agent/kg body weight will have therapeutic efficacy, with all weights being calculated based upon the weight of the active ingredient, including salts. Aerosol dosage, formulations and delivery systems may be selected as described, for example, in Gonda, "Aerosols for delivery of therapeutic and diagnostic agents to the respiratory tract," in Critical Reviews in Therapeutic Drug Carrier Systems, 6: 273-313, 1990; and in Moren, "Aerosol dosage forms and formulations," in: Aerosols in Medicine. Principles, Diagnosis and Therapy, Moren, et al., Eds, Elsevier, Amsterdam, 1985. The pharmaceutical composition can be delivered in any suitable volume or mass (weight) of administration. In representative embodiments of the invention, the administration volume of liquid particles (e.g., liquid aerosol particles) in a single administration suitable for pulmonary delivery ranges from several microliters to several milliliters (e.g., from about 3 microliters to about 3, 4 or 5 milliliters). In other particular embodiments, the mass of solid particles (e.g., solid aerosol particles) in a single administration suitable for pulmonary delivery ranges from several micrograms to several milligrams (e.g., about 3 micrograms to about 3, 4 or 5 milligrams).

Pulmonary administration of any suitable formulation known or later discovered in the art is contemplated. For example, the composition can be formulated for nasal or oral administration to the lungs. In certain embodiments, the composition is formulated for oral inhalation. In other exemplary embodiments, the composition is administered as an aerosol solution, a suspension, or a dry powder of respirable particles containing the active agent, which the subject inhales. The respirable particles can be liquid or solid; optionally, the respirable particles are a dry powder or liquid aerosol. Further, in certain embodiments the respirable particles described above can be administered by oral inhalation.

For the purposes of the present invention, the term "aerosol" includes any gas-borne suspended phase, which is capable of being inhaled into the bronchioles or nasal passages. Specifically, an aerosol includes a gas-borne suspension of droplets, as can be produced in a metered dose inhaler, nebulizer, mist sprayer, or the like. The term "aerosol" also includes a dry powder composition suspended in air or other carrier gas, which can be delivered by insufflation from an inhaler device, for example. See Ganderton & Jones, Drug Delivery to the Respiratory Tract, Ellis Horwood (1987); Gonda (1990) Critical Reviews in Therapeutic Drug Carrier Systems 6:273-313; and Raeburn, et al. (1992) J. Pharmacol. Toxicol. Methods 27:143-159. In particular embodiments, the pulmonary formulation comprises a dispersible dry powder. "Dispersibility" or "dispersible" or equivalent terms means a dry powder having a moisture content of less than about 10% by weight (% w) water, usually below about 5% w, or less than about 3% w; a particle size of about 1-5 μm mass median diameter (MMD), 1-4 μm MMD or 1-3/yrn MMD; a delivered dose of about >5%, >10%, >15%, >20%, >30%, >40% or >50%; and an aerosol particle size distribution of about 1-5//m mass median aerodynamic diameter (MMAD), 1.5-4.5 μm MMAD, or 1.5-3 μm MMAD. Methods and compositions for improving dispersibility are disclosed in U.S. Patent Nos. 6,136,346; 6,358,530 and 6,582,729. The term "powder" as used herein means a composition that consists of finely dispersed solid particles that are free flowing and capable of being readily dispersed in an inhalation device and subsequently inhaled by a subject so that the particles reach the lungs, and optionally permit penetration into the alveoli. In particular embodiments, the average particle size is less than about 10, 7.5, or 5 μm in diameter with a relatively uniform spheroidal shape distribution. Generally, the particle size distribution is between about 0.1 μm and about 5 μm, particularly about 0.3 μm to about 5 μm or about 1 μm to about 3 μm.

The term "dry" means that the composition has a moisture content such that the particles are readily dispersible in an inhalation device to form an aerosol. This moisture content is generally below about 10% by weight (% w) water, usually below about 5% w or below about 3% w.

In the dry state, the powder may be in crystalline or amorphous form. A therapeutically effective amount of active pharmaceutical will vary in the composition depending on the biological activity of the compound(s) employed and the amount needed in a unit dosage form. Because the composition is dispersible, it is generally advantageous that it is manufactured in a unit dosage form in a manner that allows for ready manipulation by the formulator and by the consumer. A unit dosage will typically be between about 0.5 mg and 15 mg, more particularly between about 2 mg and 10 mg, of total material in the dry powder composition. Aerosols of liquid particles containing the active agent can be produced by any suitable aerosolization means, such as with a pressure-driven aerosol nebulizer, an electrostatic nebulizer, an ultrasonic nebulizer, a pressured/volatile gas-filled metered dose inhaler (MDI), a piston-driven system with a grid or laser-drilled holes, or devices that rely upon the subject's inspiratory flow, as are known to those of skill in the art. See, e.g., U.S. Patent No. 4,501 ,729.

Aerosols of solid particles containing the active agent can likewise be produced with any solid particulate medicament aerosol generator, by techniques known in the pharmaceutical art. See, for example, U.S. Patent Nos. 6,169,068, U.S. Patent No. 6,334,999 and U.S. Patent No. 6,797,258.

As further examples, solid particies can be delivered from an inhalation device such as a dry powder inhaler (DPI) or a MDI. Other suitable inhalers are described in U.S. Pat. No. 4,069,819, U.S. Pat.

No. 4,995,385, and U.S. Pat. No. 5,997,848. Further examples include, but are not limited to, the Spinhaler®. (Fisons, Loughborough, U.K.), Rotahaler®. (Glaxo- Wellcome, Research Triangle Technology Park, NC), FlowCaps®. (Hovione, Loures, Portugal), Inhalator® (Boehringer-lngelheim, Germany), and the Aerolizer® (Novartis, Switzerland), the diskhaler (Glaxo-Wellcome, RTP, NC) and others, such as known to those skilled in the art.

Dry powder dispersion devices are described in a number of patent documents. U.S. Pat. No. 3,921 ,637 describes a manual pump with needles for piercing through a single capsule of powdered medicine. The use of multiple receptacle disks or strips of medication is described in European Patent Application No. EP 0 467 172 (where a reciprocatable punch is used to open a blister pack); International Patent Publication Nos. WO 91/02558 and WO 93/09832; U.S. Pat. Nos. 4,627,432; 4,811 ,731; 5,035,237; 5,048,514; 4,446,862; 5,048,514; and 4,446,862. Other patents that show puncturing of single medication capsules include U.S. Pat. Nos. 4,338,931; 3,991 ,761; 4,249,526; 4,069,819; 4,995,385; 4,889,114; and 4,884,565; and European Patent Application No. EP 469 814. International Patent Publication No. WO 90/07351 describes a hand-held pump device with a loose powder reservoir.

A dry powder sonic velocity disperser is described in Witham and Gates, Dry Dispersion with Sonic Velocity Nozzles, presented at the workshop on Dissemination Techniques for Smoke and Obscurants, Chemical Systems Laboratory, Aberdeen Proving Ground, Maryland, Mar. 14-16, 1983.

U.S. Pat. Nos. 4,926,852 and 4,790,305 describe a type of "spacer" for use with a metered dose inhaler. The spacer defines a large cylindrical volume which receives an axially directed burst of drug from a propellant-driven drug supply. U.S. Pat. No. 5,027,806 is an improvement over the '852 and '305 patents, having a conical holding chamber that receives an axial burst of drug. U.S. Pat. No. 4,624,251 describes a nebulizer connected to a mixing chamber to permit a continuous recycling of gas through the nebulizer. European Patent Application No. 0 347 779 describes an expandable spacer for a metered dose inhaler having a one-way valve on the mouthpiece. International Patent Publication No. WO 90/07351 describes a dry powder oral inhaler having a pressurized gas source (a piston pump) which draws a measured amount of powder into a venturi arrangement.

Stribling et al. (1992) J. Biopharm. Sci. 3:255-263, describes the aerosol delivery of plasmids carrying a chloramphenicol acetyltransferase (CAT) reporter gene to mice. The plasmids were incorporated in DOTMA (N-[1-(2-, 3- dioleyloxy)propyl]-N,N,N-trimethylammonium chloride) or cholesterol liposomes, and aqueous suspensions of the liposomes were nebulized into a small animal aerosol delivery chamber. Mice breathing the aerosol were found to at least transiently express CAT activity in their lung cells. Rosenfeld et al. (1991) Science: 252:431- 434, describes the in vivo delivery of an alpha-1 antitrypsin gene to rats, with secretion of the gene product being observable for at least one week. The gene was diluted in saline and instilled directly into the rat trachea.

Patton and Platz (1992) Adv. Drug Deliver. Rev. 8:179-196, describe methods for delivering proteins and polypeptides by inhalation to the deep lung. The aerosolization of protein therapeutic agents, including alpha-1 antitrypsin, is disclosed in European Patent Application No. EP 0 289 336. In general, nebulizers can be advantageous for delivery of liquid compositions comprising polypeptides, as nebulizers are gentler on the pharmaceutical composition than, for example, a MDI device. There are several considerations that bear upon the design and operation of the delivery device. To illustrate, unlike dry powder administration, for liquids it is the device that determines particle size, usually as a function of the diameter of the delivery port, mesh or grid. Liquid particles (i.e., droplets) having a desired size as described herein can be achieved by selection of a suitable delivery device based on considerations well-known in the art.

Delivery velocity is another factor to consider for pulmonary delivery. Even particles of an optimum size will rebound from the soft palate, and therefore not travel down the trachea, if they are delivered at too high a velocity. On the other hand, particles that are delivered at too slow a velocity will not enter the respiratory tract at all (e.g., in the case of oral inhalation, they will land on the tongue).

Delivery devices and methods can also be selected to time delivery of the pharmaceutical composition with the breathing cycle. Some devices incorporate firmware that measures the timing of the patient's breathing cycle and optimizes pulsed drug delivery to achieve efficient delivery. More commonly, devices (included pulsed nebulizers, MDIs and dry powder devices) rely on a learned coordination by the patient of drug delivery with inspiration. MDIs are available that provide a mixing cylinder placed between the delivery device and the mouthpiece to improve dispersion of the aerosol and reduce the need to time delivery with the breathing cycle.

As yet another approach, some devices incorporate a heating device to warm the pharmaceutical composition to body temperature during delivery, which results in more efficient pulmonary delivery.

The compositions of the invention can be formulated for pulmonary administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (20^th edition, 2000). Suitable nontoxic pharmaceutically acceptable carriers for pulmonary administration will be apparent to those skilled in the art of pulmonary pharmaceutical formulations (see, e.g., Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton latest edition).

The composition may optionally be combined with pharmaceutical carriers or excipients that are suitable for pulmonary administration. Such carriers may serve simply as bulking agents when it is desired to reduce the pharmaceutical concentration in the powder which is being delivered to a patient, but may also serve to enhance the stability of the compositions and to improve the dispersibility of the powder within a powder dispersion device in order to provide more efficient and reproducible delivery of the powder and to improve handling characteristics such as flowability and consistency to facilitate manufacturing and powder filling.

Such carrier materials may be combined with the drug prior to spray drying, e.g., by adding the carrier material to the purified bulk solution. In that way, the carrier particles will be formed simultaneously with the drug particles to produce a homogeneous powder. Alternatively, the carriers may be separately prepared in a dry powder form and combined with the dry powder drug by blending. The powder carriers will usually be crystalline (to avoid water absorption), but might in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles may be selected to improve the flowability of the drug powder, typically being in the range from about 25 μm to 100 μm. One suitable carrier material is crystalline lactose having a size in the above-stated range.

The active compound(s) can be present in the formulation in any suitable amount, for example, a range from about 0.05, 0.1 , 0.5 or 1% to about 50, 60, 70, 80, 90, 95, 97 or 99% (w/w or w/v).

The compound can have any suitable molecular weight. According to certain embodiments of the invention, the compound has a molecular weight of about 10 kilodaltons or less, 7.5 kilodaltons or less, 5 kilodaltons or less, 2 kilodaltons or less, 1 kilodalton or less, 500 daltons or less. The pharmaceutical composition can further have any suitable osmolarity, for example, in the range of about 100 to 600 mOsM, about 150 to 450 mOsM, or about 175 to 31O mOsM.

The formulation can further comprise one or more component(s) that promote(s) the fast release of the active compound(s) into the blood stream. In one embodiment, a therapeutic plasma concentration is achieved in less than about 10 minutes, 5 minutes, 2 minutes or even sooner after administration.

In particular embodiments, the formulation includes one or more phospholipids, such as, for example, a phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol or a combination thereof. For example, the phospholipids can be endogenous to the lung. Combinations of phospholipids can also be employed. Specific examples of phospholipids are shown in Table I.

TABLE I

Dilaurylolyphosphatidylcholine (C12; 0) DLPC

Dimyristoylphosphatidylcholine (C14; 0) DMPC

Dipalmitoylphosphatidylcholine (C16:0) DPPC Distearoylphosphatidylcholine (18:0) DSPC

Dioleoylphosphatidylcholine (C18:1) DOPC

Dilaurylolylphosphatidylglycerol DLPG

Dimyristoylphosphatidylglycerol DMPG

Dipalmitoylphosphatidylglycerol DPPG Distearoylphosphatidylglycerol DSPG

Dioleoylphosphatidylglycerol DOPG

Dimyristoyl phosphatidic acid DMPA

Dipalmitoyl phosphatidic acid DPPA Dipalmitoyl phosphatidic acid DPPA

Dimyristoyl phosphatidylethanolamine DMPE

Dipalmitoyl phosphatidylethanolamine DPPE

Dimyristoyl phosphatidylserine DMPS

Dipalmitoyl phosphatidylserine DPPS Dipalmitoyl sphingomyelin DPSP

Distearoyl sphingomyelin DSSP The phospholipid can be present in the formulation in any suitable amount, e.g., an amount ranging from about 0, 1, 5 or 10% to about 50, 60, 70, 80 or 90% (w/w or w/v).

The phospholipids or combinations thereof can be selected to impart rapid or controlled-release properties to the formulation. Particles having controlled-release properties and methods of modulating release of a biologically active agent are described in U.S. patent application Ser. No. 09/644,736 and U.S. patent Publication No. 20010036481. Rapid release can be obtained, for example, by including in the formulation phospholipids characterized by low transition temperatures. Rapid release can also be achieved by administering formulations comprising nanoparticles (e.g., because of large surface area) and formulations in the form of solutions.

Nanoparticles, microspheres, cyclodextrins and liposomes can be used as vehicles for controlled-release delivery. In another embodiment, rapid and controlled-release of the active compound(s) are coupled in a single course of therapy.

The formulation can further include a surfactant. As used herein, the term "surfactant" refers to any agent that preferentially absorbs to an interface between two immiscible phases, such as the interface between water and an organic polymer solution, a water/air interface or organic solvent/air interface. Surfactants generally possess a hydrophilic moiety and a lipophilic moiety, such that, upon absorbing to microparticles, they tend to present moieties to the external environment that do not attract similarly-coated particles, thus reducing particle agglomeration. Surfactants may also promote absorption of a therapeutic or diagnostic agent and increase bioavailability of the agent.

In addition to lung surfactants, such as, for example, the phospholipids discussed above, suitable surfactants include but are not limited to hexadecanol; fatty alcohols such as polyethylene glycol (PEG) and acetyl alcohol; polyoxyethylene- 9-lauryl ether; a surface active fatty acid, such as palmitic acid or oleic acid; glycocholate; surfactin; a poloxomer; a sorbitan fatty acid ester such as sorbitan trioleate (Span 85); and tyloxapol.

The surfactant can be present in the formulation in any suitable amount, for example, an amount ranging from about 0, 1 , 5 or 10% to about 50, 60, 70, 80 or 90% (w/w or w/v). Methods of preparing and administering particles including surfactants, in particular phospholipids, are disclosed in U.S. Pat. No 5,855,913 and U.S. Pat. No. 5,985,309. Additives can be included for conformational stability during spray drying and for improving dispersibility of powders. One such group of additives includes amino acid(s), in particular, hydrophobic amino acid(s). Suitable amino acids include naturally occurring and non-naturally occurring amino acids. Specific examples of amino acids which can be employed include, but are not limited to: alanine, glycine, praline, cysteine, methionine, valine, leucine, tyrosine, isoleucine, phenylalanine, and tryptophan. Non-naturally occurring amino acids include, for example, β-amino acids. Both D, L and racemic configurations of amino acids can be employed. Suitable amino acids can also include amino acid analogs. As used herein, an amino acid analog includes the D or L configuration of an amino acid having the following formula: -NH-CHR-CO- wherein R is an aliphatic group, a substituted aliphatic group, a benzyl group, a substituted benzyl group, an aromatic group or a substituted aromatic group and wherein R does not correspond to the side chain of a naturally- occurring amino acid. As used herein, aliphatic groups include straight chained, branched or cyclic CI-C8 hydrocarbons which are completely saturated, which contain one or two heteroatoms such as nitrogen, oxygen or sulfur and/or which contain one or more units of unsaturation. Aromatic groups include carbocyclic aromatic groups such as phenyl and naphthyl and heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl, furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl and acridintyl.

Suitable substituents on an aliphatic, aromatic or benzyl group include -OH, halogen (-Br, -Cl, -I and -F) -O(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), -CN, -NO₂, -COOH, -NH₂, - NH(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), -N(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group)₂, -COO(aliphatic group, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group), -CONH₂, -CONH(aliphatic, substituted aliphatic group, benzyl, substituted benzyl, aryl or substituted aryl group), -SH, -S(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic group) and -NH-C(=NH)-NH₂. A substituted benzylic or aromatic group can also have an aliphatic or substituted aliphatic group as a substituent. A substituted aliphatic group can also have a benzyl, substituted benzyl, aryl or substituted aryl group as a substituent. A substituted aliphatic, substituted aromatic or substituted benzyl group can have one or more substituents. Modifying an amino acid substituent can increase, for example, the lipophilicity or hydrophobicity of natural amino acids that are hydrophilic. A number of suitable amino acids, amino acid analogs and salts thereof can be obtained commercially. Others can be synthesized by methods known in the art. Synthetic techniques are described, for example, in Green and Wuts, "Protecting Groups in Organic Synthesis", John Wiley and Sons, Chapters 5 and 7, 1991. Hydrophobicity is generally defined with respect to the partition of an amino acid between a nonpolar solvent and water. Hydrophobic amino acids are those amino acids that show a preference for the nonpolar solvent. Relative hydrophobicity of amino acids can be expressed on a hydrophobicity scale on which glycine has the value 0.5. On such a scale, amino acids that have a preference for water have values below 0.5 and those that have a preference for nonpolar solvents have a value above 0.5. As used herein, the term "hydrophobic amino acid" refers to an amino acid that on the hydrophobicity scale has a value greater or equal to 0.5, in other words, has a tendency to partition in the nonpolar solvent that is at least equal to that of glycine.

In representative embodiments, combinations of hydrophobic amino acids are employed. Furthermore, in other embodiments, combinations of hydrophobic and hydrophilic (preferentially partitioning in water) amino acids, where the overall combination is hydrophobic, are employed.

The amino acid can be present in the pulmonary formulations in any suitable amount, for example, an amount of at least about 10% (w/w or w/v). In particular embodiments, the amino acid is present in the formulation in an amount ranging from about 20% to about 80% (w/w or w/v). The salt of a hydrophobic amino acid can be present in the formulation in any suitable amount, for example, an amount of at least about 10% (w/w or w/v). In illustrative embodiments, the amino acid salt is present in the formulation in an amount ranging from about 20% to about 80% (w/w or w/v). Methods of forming and delivering particles that include an amino acid are described in U.S. Patent No. 6,586,008 and U.S. patent application Ser. No. 09/644,320.

In another embodiment of the invention, the formulation includes a carboxylate moiety and/or a multivalent metal salt. Such compositions are described, for example, in U.S. Patent No. 6,749,835. In one particular embodiment, the formulation includes sodium citrate and/or calcium chloride.

The pulmonary formulation can further comprise carriers including but not limited to stabilizers such as human serum albumin (HSA), bulking agents such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; salts such as sodium chloride; and the like. These carriers may be in a crystalline or amorphous form or may be a mixture of the two.

Bulking agents include compatible carbohydrates, polypeptides, amino acids or combinations thereof. Suitable carbohydrates include monosaccharides such as galactose, D-mannose, sorbose, and the like; disaccharides, such as lactose, trehalose, and the like; cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides, such as raffinose, maltodextrins, dextrans, and the like; alditols, such as mannitol, xylitol, and the like. Suitable polypeptides include aspartame. Amino acids include alanine and glycine.

The pharmaceutical composition can have any suitable pH. In representative embodiments, the pH of the pharmaceutical composition ranges from about 4, 4.5, 5 or 5.5 to about 6, 6.5, 7, 7.5 or 8. Exemplary pH ranges include without limitation from about pH 4.5 to about pH 8 and from about pH 5.5 to about pH 7.5. Those skilled in the art will appreciate that because the volume of the pharmaceutical composition administered is generally small (e.g., less than 5 milliliters), secretions from the respiratory tract may alter the pH of the administered dose. Such alterations can affect the concentration of un-ionized drug available for absorption. Accordingly, in representative embodiments, the pharmaceutical composition further comprises a buffer to maintain or regulate pH in situ. Typical buffers include but are not limited to organic salts, e.g., prepared from organic acids and bases, such as acetate, citrate, prolamine, carbonate, ascorbate and phosphate buffers.

Other materials, including materials that promote fast release kinetics of the active compound can also be employed. For example, biocompatible, and optionally biodegradable polymers can be employed. Illustrative formulations including such polymeric materials are described in U.S. Pat. No. 5,874,064.

The formulation can further include a material such as, for example, dextran, polysaccharides, lactose, trehalose, cyclodextrins, proteins, peptides, polypeptides, fatty acids, inorganic compounds and/or phosphates. To extend shelf life, preservatives can optionally be added to the pharmaceutical composition. Suitable preservatives include but are not limited to benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium chloride, and combinations of the foregoing. The concentration of the preservative will vary depending upon the preservative used, the compound being formulated, the formulation, and the like. In representative embodiments, the preservative is present in an amount of 2% by weight or less. In certain embodiments, the pharmaceutical composition is sufficiently stable as to not require the addition of preservatives. The absence of preservatives can be advantageous since preservatives may raise safety and toxicity issues, especially to the lung. In particular embodiments, the formulation is substantially free of any penetration enhancers. The use of penetration enhancers in formulations for the lungs is often undesirable because the epithelial cell layer in the lung can be adversely affected by such surface active compounds.

As another option, the composition can comprise a flavoring agent, e.g., to enhance the taste and/or acceptability of the composition to the subject. In the case of active compounds comprising polypeptides, it is generally desirable that the compound be shielded from leukocyte proteases in the lung and/or have a structure that is resistant to proteolytic degradation. To illustrate, the compound can be protected from proteolytic cleavage by encapsulation, for example, in lysosomes. As another option, the compound can be formulated with a protease inhibitor, such as benzamidine or a derivative thereof (see, e.g., Pauls et al., (2004) Front. Med. Chem. 1 :129-152). As still another approach, polypeptides can be synthesized with modified peptide bonds and/or with blocked or otherwise modified amino and/or carboxyl termini that are resistant to proteolytic cleavage.

In representative embodiments, the active compound is lipophilic to promote absorption. In general, nonpolar compounds more readily cross the mucosal lining and the epithelial cell layer in the lungs. In other embodiments, uptake of non- lipophilic compounds is enhanced by combination with a lipophilic substance. Lipophilic substances that can enhance absorption of the compound include but are not limited to esters, fatty acids (e.g., palmitic acid), gangliosides (e.g., GM-I), phospholipids (e.g., phosphatidylserine), and emulsifiers (e.g., polysorbate 80), bile salts such as sodium deoxycholate, and detergent-like substances including, for example, polysorbate 80 such as Tween™, octoxynol such as Triton™ X-100, and sodium tauro-24,25-dihydrofusidate (STDHF). See Lee et al., Biopharm., April 1988 issue:3037. In particular embodiments of the invention, the active compound is combined with micelles comprised of lipophilic substances, e.g., to achieve a uniform emulsion. Such micelles can modify the permeability of the alveoli membrane to enhance absorption of the compound. Suitable lipophilic micelles include without limitation gangliosides (e.g., GM-1 ganglioside), and phospholipids (e.g., phosphatidylserine). Bile salts and their derivatives and detergent-like substances can also be included in the micelle formulation. The active compound can be combined with one or several types of micelles, and can further be contained within the micelles or associated with their surface.

Alternatively, the active compound can be combined with liposomes (lipid vesicles) to enhance absorption. The active compound can be contained or dissolved within the liposome and/or associated with its surface. Suitable liposomes include phospholipids (e.g., phosphatidylserine) and/or gangliosides (e.g., GM-1). For methods of making phospholipid vesicles, see for example, U.S. Patent 4,921 ,706 to Roberts et al., and U.S. Patent 4,895,452 to Yioumas et al. Bile salts and their derivatives and detergent-like substances can also be included in the liposome formulation. The pharmaceutical composition can be formulated to enhance delivery to the desired target regions, e.g., the deep lung or alveoli. In particular embodiments, the liquid or dry powder particles, optionally liquid or dry powder aerosol particles, have a tap density less than about 0.4, 0.2 or even 0.1 g/cm³. Particles that have a tap density of less than about 0.4 g/cm³ are referred to herein as "aerodynamically light particles". Tap density can be measured by using instruments known to those skilled in the art such as but not limited to the Dual Platform Microprocessor Controlled Tap Density Tester (Vankel, NC) or a GeoPyc™ instrument (Micrometrics Instrument Corp., Norcross, GA). Tap density is a standard measure of the envelope mass density. Tap density can be determined using the method of USP Bulk Density and Tapped Density, United States Pharmacopeia convention, Rockville, Md., 10^th Supplement, 4950-4951 , 1999. Features that can contribute to low tap density include irregular surface texture and porous structure.

The envelope mass density of an isotropic particle is defined as the mass of the particle divided by the minimum sphere envelope volume within which it can be enclosed. In one embodiment of the invention, the particles have an envelope mass density of less than about 0.4 g/cm³.

In particular embodiments, aerodynamically light particles have a size, e.g., a volume median geometric diameter (VMGD), of at least about 5 μm. In one embodiment, the VMGD is from about 5μm to about 30 μm. In another embodiment of the invention, the particles have a VMGD ranging from about 10 μm to about 30 μm. In other embodiments, the particles have a median diameter, mass median diameter (MMD), a mass median envelope diameter (MMED) or a mass median geometric diameter (MMGD) of at least 5 μm, for example from about 5 μm to about 30 μm. The diameter of spray-dried particles, for example, the VMGD, can be measured using an electrical zone sensing instrument such as a Multisizer lie, (Coulter Electronic, Luton, Beds, England), or a laser diffraction instrument (for example Helos, manufactured by Sympatec, Princeton, N.J.). Other instruments for measuring particle diameter are well known in the art. The diameter of particles in a sample will range depending upon factors such as particle composition and methods of synthesis. The distribution of size of particles in a sample can be selected to permit optimal deposition to targeted sites within the lungs. In representative embodiments, aerodynamically light liquid or dry powder particles have a "mass median aerodynamic diameter" (MMAD), also referred to herein as "aerodynamic diameter", between about 1 μm and about 5 μm. In another embodiment of the invention, the MMAD is between about 1 μm and about 3 μm. In a further embodiment, the MMAD is between about 3 μm and about 5 μm.

Experimentally, aerodynamic diameter can be determined by employing a gravitational settling method, whereby the time for an ensemble of particles to settle a certain distance is used to infer directly the aerodynamic diameter of the particles. An indirect method for measuring the mass median aerodynamic diameter (MMAD) is the multi-stage liquid impinger (MSLI).

The aerodynamic diameter, d_aer, can be calculated from the equation:

where d_g is the geometric diameter, for example the MMGD, and p is the powder density.

Particles that have a tap density less than about 0.4 g/cm³, a median geometric diameter of at least about 5 μm, and/or an MMAD of between about 1 μm and about 3 or 5 μm, are more likely of escaping inertial and gravitational deposition in the oropharyngeal region, and are targeted to the airways, particularly the deep lung. In particular embodiments, the use of larger, more porous particles can be advantageous since they are generally able to aerosolize more efficiently than smaller, denser aerosol particles. In certain embodiments of the invention, such larger more porous particles are used as a vehicle for the delivery of dry powders.

In other representative embodiments, larger particles which are less porous, but which are effectively microspheres containing a suspension of dry particles or droplets, may also possess a density less than about 0.4 g/cm³, or preferably less than about 0.15 g/cm³. Such particles are most efficiently delivered to the deep lung if they possess a geometric diameter from about 4 μm to greater than about 8 μm.

In embodiments of the invention, the particles have an MMAD of about 1 to 5 μm, more particularly about 1 to 3 μm. The particles can be liquid or dry powder. In embodiments in which the particles to be delivered are composed of an aerosol generated from a liquid (e.g., from an aqueous solution), the particles generally have a density greater than 1 g/cm³ and less than about 1.2 g/cm³. In these embodiments, the particles typically have a geometric diameter ranging from about 1 μm to about 5 μm or from about 1 μm to about 3 μm for delivery to the deep lung or alveoli. In other embodiments, the particles generally have a median diameter of at least about 5 μm, and more particularly about 15-20 μm, and are generally more likely to avoid phagocytic engulfment by alveolar macrophages and clearance from the lungs, due to size exclusion of the particles from the phagocytes cytosolic space. According to this embodiment, the particles generally have a low density, e.g., dry powder particles or a suspension of microspheres.

The particles can be fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions of the lungs such as the deep lung or upper or central airways. For example, higher density or larger particles may be used for upper airway delivery, or a mixture of varying sized particles in a sample, provided with the same or different therapeutic agent may be administered to target different regions of the lung in one administration. Particles having an MMAD ranging from about 3 to about 5 μm are generally suitable for delivery to the central and upper airways. Particles having an MMAD ranging from about 1 to about 3 μm or about 5 μm are generally suitable for delivery to the deep lung, lnertial impaction and gravitational settling of aerosols are predominant deposition mechanisms in the airways and acini of the lungs during normal breathing conditions. Edwards, D. A., J Aerosol ScL, 26: 293-317 (1995). The importance of both deposition mechanisms increases in proportion to the mass of aerosols and not to particle (or envelope) volume. Since the site of aerosol deposition in the lungs is influenced by the mass of the aerosol (at least for particles of mean aerodynamic diameter greater than approximately 1 μm), diminishing the tap density by increasing particle surface irregularities and particle porosity permits the delivery of larger particle envelope volumes into the lungs, all other physical parameters being equal. The low tap density particles have a small aerodynamic diameter in comparison to the actual envelope sphere diameter. The aerodynamic diameter, d_aΘr, is related to the envelope sphere diameter, d (Gonda, I., "Physico-chemical principles in aerosol delivery," in Topics in Pharmaceutical Sciences 1991 (eds. D. J. A. Crommelin and K. K. Midha), pp. 95-117, Stuttgart: Medpharm Scientific Publishers, 1992)), by the formula:

where the envelope mass p is in units of g/cm³. Maximal deposition of monodispersed aerosol particles in the alveolar region of the human lung (-60%) occurs for an aerodynamic diameter of approximately d_aer = 3 μm. Heyder, J. et al., J Aerosol ScL, 17: 811-825 (1986). Due to their small envelope mass density, the actual diameter d of aerodynamically light particles comprising a monodisperse inhaled powder that will exhibit maximum deep-lung deposition is:

d = 3/vyo μm (where p <1 g/cm³);

where d is greater than 3 μm. For example, aerodynamically light particles that display an envelope mass density, p = 0.1 g/cm³, will exhibit a maximum deposition for particles having envelope diameters as large as 9.5 μm. The increased particle size diminishes interparticle adhesion forces. Visser, J., Powder Technology, 58: 1-10. Thus, large particle size generally increases efficiency of aerosolization to the deep lung for particles of low envelope mass density, in addition to contributing to lower phagocytic losses.

The aerodynamic diameter can be calculated to provide for maximum deposition within the lungs. Previously this was achieved by the use of very small particles of less than about five microns in diameter, preferably between about one and about three microns, which particles may then be subject to phagocytosis.- For the delivery of formulations composed of microspheres or particles formulated for the delivery of a dry powder, particles that have a larger diameter, but that are sufficiently light (hence the characterization "aerodynamically light"), can result in an equivalent delivery to the lungs, with a lower susceptibility to phagocystosis. Improved delivery can be obtained by using particles with a rough or uneven surface, which also have a lower susceptibility for phagocystosis. In another embodiment of the invention, the particles have an envelope mass density, also referred to herein as "mass density" of less than about 0.4 g/cm³. In particular embodiments, particles have a mean diameter of between about 5 μm and about 30 μm. Mass density and the relationship between mass density, mean diameter and aerodynamic diameter are discussed in U.S. application Ser. No. 08/655,570. In a representative embodiment, the particles have a mass density less than about 0.4 g/cm³, a mean geometric diameter of between about 5 μm and about 30 μm and MMAD between about 1 μm and about 5 μm.

Suitable particles can be fabricated or separated, for example by filtration or centrifugation, to provide a particle sample with a preselected size distribution. For example, greater than about 30%, 50%, 70%, 80%, 90% or 95% of the particles in a sample can have a diameter within a selected range of at least about 5 μm. The selected range within which a certain percentage of the particles fall may be for example, between about 5 and about 30 μm, or between about 5 and about 15μm. In one embodiment, at least a portion of the particles have a diameter between about 9 and about 11 μm. Optionally, the particle sample also can be fabricated wherein at least about 75%, 85%, 90%, or optionally about 95% or about 99%, have a diameter within the selected range. The presence of the higher proportion of the aerodynamically light, larger diameter particles in the particle sample can enhance the delivery of therapeutic or diagnostic agents incorporated therein to the deep lung. Large diameter particles generally mean particles having a median geometric diameter of at least about 5 μm. Properties of the particles facilitate delivery to subjects with highly compromised lungs where other particles prove ineffective for those lacking the capacity to strongly inhale, such as young patients, old subjects, infirm subjects, or subjects with asthma or other breathing difficulties. Further, subjects suffering from a combination of ailments may simply lack the ability to sufficiently inhale. Thus, using the methods and particles described above, even a weak inhalation is sufficient to deliver the desired dose.

Alternatively, in other embodiments, smaller high-density particles that have sufficient momentum to achieve deep lung or alveoli delivery can be used.

Particles can be prepared by any method known in the art. In representative embodiments, suitable particles are fabricated by spray drying. The spray drying can be done under conditions that result in a substantially amorphous powder of homogeneous constitution having a particle size that is respirable, a low moisture content and flow characteristics that allow for ready aerosolization.

In one embodiment, the method includes forming a mixture including one or more compounds of the invention and a surfactant, such as, for example, the surfactants described above. The mixture employed in spray drying can include an organic or aqueous-organic solvent.

Suitable organic solvents that can be employed include but are not limited to alcohols for example, ethanol, methanol, propanol, isopropanol, butanols, and others. Other organic solvents include but are not limited to perfluorocarbons, dichloromethane, chloroform, ether, ethyl acetate, methyl tert-butyl ether and others. Co-solvents include an aqueous solvent and an organic solvent, such as, but not limited to, the organic solvents as described above. Aqueous solvents include water and buffered solutions. In one embodiment, an ethanol water solvent is preferred with the ethanol:water ratio ranging from about 50:50 to about 90:10 ethanol:water. The spray drying mixture can have a neutral, acidic or alkaline pH (e.g., from about pH 3 to about pH 10). Optionally, a pH buffer can be added to the solvent or co-solvent or to the formed mixture.

Suitable spray-drying techniques are described, for example, by K. Masters in "Spray Drying Handbook", John Wiley & Sons, New York, 1984. Generally, during spray-drying, heat from a hot gas such as heated air or nitrogen is used to evaporate the solvent from droplets formed by atomizing a continuous liquid feed. Other spray- drying techniques are well known to those skilled in the art. In a preferred embodiment, a rotary atomizer is employed. An example of suitable spray driers using rotary atomization includes the Mobile Minor spray drier, manufactured by Niro, Denmark. The hot gas can be, for example, air, nitrogen or argon.

The particles can be fabricated with a rough surface texture to reduce particle agglomeration and improve flowability of the powder. The spray-dried particles can have improved aerosolization properties. The spray-dried particle can be fabricated with features which enhance aerosolization via dry powder inhaler devices, and lead to lower deposition in the mouth, throat and inhaler device.

Alternatively, dry powder compositions may be prepared by other processes such as lyophilization and jet milling as disclosed in International Patent Publication No. WO 91/16038. In other embodiments of the invention, the formulation is administered to the lungs as a liquid, an emulsion, or a dispersion. Liquid-born agents can be delivered to the lungs by any method known in the art, e.g., by recirculation in and out of the lungs (e.g., by liquid lavage or liquid ventilation) or maintained in a static system {i.e., non-recirculated) for extended periods of time. For example, in representative embodiments, a liquid can be instilled via a lavage tube. As another option, a liquid aerosol can be instilled via a respirator.

U.S. Patent No. 6,242,472 describes the delivery of therapeutic agents in a liquid carrier such as saline, silicone, vegetable oil or perfluorochemicals (e.g., perfluorocarbon), e.g., in the form of an emulsion or a dispersion, for delivery to the pulmonary air passages.

The active compound can be present in the liquid in any suitable form, e.g., bulk form, a suspension, a dispersion, a liquid form, an emulsion, and/or an encapsulized form. Moreover, the selected compound(s) can be incorporated into the liquid medium by any suitable technique. Examples of suitable incorporation techniques include, but are not limited to, injection, blending, or dissolving.

Liquids can be selectively directed to specific regions of the subject's lungs by a number of conventional means, such as a bronchoscope or a catheter. The methods of delivery to the lungs can be carried out once or multiple times, and can further be carried out daily, every other day, etc., with a single administration or multiple administrations per day of administration, (e.g., 2, 3, 4 or more times per day of administration). In representative embodiments, the methods of the invention can be carried out on an as-needed basis by self-medication.

In particular embodiments, the methods of the invention comprise administering to the pulmonary system a therapeutic dose in a small number of breath-activated steps (e.g., less than 5, 4, or 3), and even in one or two breath- activated step(s). Particular methods include administering particles from a receptacle having, holding, containing, storing or enclosing a mass of particles, to a subject's lungs. In one example, at least 50% of the mass of the particles stored in the inhaler receptacle is delivered to a subject's lungs in a single, breath-activated step. In another embodiment, at least 10 milligrams of the active compound(s) is delivered by administering, in a single breath, to a subject's lungs particles enclosed in the receptacle. Amounts as high as 15, 20, 25, 30, 35, 40 and 50 milligrams or more can be delivered.

In one embodiment, delivery to the pulmonary system of particles in a single, breath-actuated step is enhanced by employing particles that are dispersed at relatively low energies, such as, for example, at energies typically supplied by a subject's inhalation. Such energies are referred to herein as "low." As used herein, "low energy administration" refers to administration wherein the energy applied to disperse and/or inhale the particles is in the range typically supplied by a subject during inhaling. The pharmaceutical compositions of the present invention can optionally be administered in conjunction with other therapeutic agents, for example, other therapeutic agents useful in the treatment of hyperglycemia, diabetes, metabolic syndrome and/or obesity. For example, the compounds of the invention can be administered in conjunction with insulin therapy and/or hypoglycemic agents (e.g., metformin). The additional therapeutic agent(s) can optionally be administered concurrently (as described above) with the compounds of the invention, in the same or different formulations.

The invention also encompasses a pulmonary delivery device comprising one or more compounds of the invention (optionally as a pharmaceutical composition). The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

What is claimed is:

1. A pharmaceutical composition formulated for intranasal delivery to the upper third of the nasal cavity or for pulmonary delivery to the lung, wherein the pharmaceutical composition comprises a compound that reduces protein tyrosine phosphatase 1 B (PTP1 B) activity in a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for intranasal delivery to the olfactory region and/or sinus region.

3. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition is formulated for intranasal delivery to the upper third of the nasal cavity.

4. The pharmaceutical composition of claim 2, wherein the compound is an inhibitor of PTP1 B enzymatic activity.

5. The pharmaceutical composition of claim 2, wherein intranasal delivery of the compound reduces PTP1 B activity in the hypothalamus, optionally the arcuate nucleus of the hypothalamus.

6. The pharmaceutical composition of claim 2, wherein the composition is an aqueous solution.

7. The pharmaceutical composition of claim 6, wherein the aqueous solution is selected from the group consisting of an aqueous gel, an aqueous suspension, an aqueous microsphere suspension, an aqueous microsphere dispersion, an aqueous liposomal dispersion, aqueous micelles of liposomes, an aqueous microemulsion, and any combination of the foregoing.

8. The pharmaceutical composition of claim 2, wherein the composition is a nonaqueous solution.

9. The pharmaceutical composition of claim 8, wherein the nonaqueous solution is selected from the group consisting of a nonaqueous gel, a nonaqueous suspension, a nonaqueous microsphere suspension, a nonaqueous microsphere dispersion, a nonaqueous liposomal dispersion, a nonaqueous emulsion, a nonaqueous microemulsion, and any combination of the foregoing.

10. The pharmaceutical composition of claim 2, wherein the composition is a powder formulation.

11. The pharmaceutical composition of claim 9, wherein the powder formulation is selected from the group consisting of a simple powder mixture, a micronized powder, powder microspheres, coated powder microspheres, and any combination of the foregoing.

12. The pharmaceutical composition of claim 2, wherein the pharmaceutical composition has a pH in the range from pH 3.5 to pH 7.

13. The pharmaceutical composition of claim 2, wherein the osmolarity of the composition is in the range from 150 to 550 mOsM.

14. The pharmaceutical composition of claim 2, wherein the composition is in the form of liquid droplets or solid particles.

15. The pharmaceutical composition of claim 14, wherein the majority and/or mean size of the liquid droplets or solid particles range in size from 5 microns to 50 microns.

16. The pharmaceutical composition of claim 15, wherein the majority and/or mean size of the liquid droplets or solid particles range in size from 10 microns to 30 microns.

17. The pharmaceutical composition of claim 2, wherein the composition is in the form of a nasal spray.

18. The pharmaceutical composition of claim 2, wherein the compound has a molecular weight of 50,000 daltons or less.

19. The pharmaceutical composition of claim 2, wherein the composition comprises at least one absorption enhancer.

20. The pharmaceutical composition of 2, wherein the composition comprises an inhibitory nucleic acid.

21. The method of claim 20, wherein the inhibitory nucleic acid is selected from the group consisting of an antisense RNA, an interfering RNA (RNAi), an aptamer, and a ribozyme.

22. The pharmaceutical composition of claim 2, wherein the composition comprises a nucleic acid selected from the group consisting of a nucleic acid that encodes an antisense RNA, a nucleic acid that encodes an RNAi, a nucleic acid that encodes an aptamer, and a nucleic acid that encodes a ribozyme.

23. The pharmaceutical composition of claim 2, wherein the compound comprises a non-hydrolysable phosphotyrosine mimetic containing peptide, a difluoromethylene phosphonate, a 2-carbomethoxybenzoid acid, a 2- oxalylaminobenzoic acid, a lipophilic compound or a peptidomimetic.

24. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (I) being:

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆; R₂ is R₅;

X is — O — C^alkylene-, — NR₈ — Ci-₃alkylene-, — S — Cr₃alkylene-, C^alkylene-, — SO₂ — C_r3alkylene-, — C₁-₄alkylene-, — C₂-₄alkenylene-, — C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q;

Y is absent, — O — , or — NR₆ — ; R₃ is H, halogen, CN, CF₃, OCF₃, C_r3alkyl, C_3-4cycloalkyl, C_r3alkoxy, or aryl; R₄ is A-B-E-D, where A is absent or arylene, heteroarylene, C_1-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl, each A being optionally substituted with one or more of C₁- ₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q; where any of the alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q; and each A being optionally terminated with one or more arylene, alkylene, or alkenylene;

B is absent or -NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)- -N(R₉)C(O)- -N(R₉)C(O)C(R₁₁)(R₁₂)-, -N(R₉)C(O)C(O)-, - N(R₉)C(O)N(R₁₀)- -N(R)SO₂-, -N(R₉)SO₂C(R₁₀)(R₁₁)- — N(R₉)(R₁₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -0-, -0-C(R₁₁)(R₁₂), -0-C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂J-O-, -C(R₁₁)(R₁₂J-O- C(Ri₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)- -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)-, — C(R₁₁)(R₁₂)S- -C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)-, Or-C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-;

E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Cr^alkylene, C₂-₁₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_1-3alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂;

D is one or more H, halogen, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, Or-S(O)_nR₇, where n is 0, 1, or 2; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-i₂alkenyl, C_2-12alkynyl,

C_3-12cycloalkyl, C_1-12alkoxyC_1-12alkyl, cycloalkylCrealkyl, 3- to 8-membered heterocycyl, heterocycylC-realkyl, aryl, arylCr₆ alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl, where each R₅, R₆, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁-NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂;

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆; and each R₉, R₁₀, R₁₁, R_i2, R₁₃ and R₁₄ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

25. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (I) being:

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆;

R₂ is R₅;

X is — O — d-aalkylene-, — NR₈ — C_r3alkylene-, — S — Crsalkylene-, — SO — C_r3alkylene-, — SO₂ — Cr₃alkylene-, — C^alkylene-, — C₂-₄alkenylene-, — C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q;

Y is absent, — O — , or -NR₆ — ; R₃ is H, halogen, CN, CF₃, OCF₃, C_halky!, C^cycloalkyl, Crsalkoxy, or aryl;

B is absent or -NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-, -N(R₉)C(O)-, -N(R₉)C(O)C(R₁₁)(R₁₂)- -N(R₉)C(O)C(O)-, — N(R₉)C(O)N(R₁₀)- -N(R)SO₂-, -N(R₉)SO₂C(R₁₀)(R₁₁)- — N(R₉)(R₁₀)C(R₁₁)(R₁₂)-, -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -O- -0-C(R₁₁)(R₁₂), -0-C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂J-O-, -C(R₁₁)(R₁₂J-O- C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)-, -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)- - C(R₁₁)(R₁₂)S-, -C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)- Or-C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-;

E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Cr₁₂alkylene, C₂-|₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_1-3alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂;

D is one or more H, halogen, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, Or -S(O)_nR₇, where n is O, 1 , or 2; subject to the proviso that when A, B, and E are absent, R₁ is C(O)OH or C(O)OCH₃, R₂ is H, and R₃ is H or chlorine, D is not H or chlorine; and when A, B, and E are absent, Ri is C(O)OH or C(O)OCH₃, R₂ is H, and R₃ is H or bromine, D is not H or bromine; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, C^alkoxyC^alkyl, cycloalkylCrealkyl, 3- to 8-membered heterocycyl, heterocycylCrβalkyl, aryl, arylC-rδalkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl, where each R₅, R₆, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁-NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂;

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆; and each R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

26. The pharmaceutical composition of claim 24, wherein the compound has a structure of formula (II), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (II) being:

(II)

27. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

("I)

wherein Ri is C(O)OR₇, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈;

R₂ is C(O)ZR₄Or CN; Z is — O— or — N R₅-;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3aikylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂₁ R₄₁ Or Q; each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O; where one or two of Y₁, Y₂, Y₃, Y₄, and Y₅ can be absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, —

C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, —

NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C₁.₁₆alkyl, C_2-12alkenyl, C_2-i₂alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^ ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₉, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C^alkyl, C_1-12alkenyl, C^^alkynyl, C_3-i₂cycloalkyl, aryl, or arylC_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

28. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being: (III)

R₂ is C(O)ZR₄Or CN; Z is — O — or — N R₅-;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C^alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O; where one or two Of Y₁, Y₂, Y₃, Y₄, and Y₅ can be absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN₁ OCF₃, OH₁ NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, —

NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C_2-i₂alkynyl,

C_3-8cycloalkyl, cycloalkylC^alkyl, 5- to 8-membered heterocycle, heterocyclicC-i.

₆alkyl, aryl, arylC_1-6alkyl, arylC₂.₆alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more Ci_-6alkyl, C₂.₆alkenyl, C₂.₆alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₉, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_1-12alkenyl, C_1-12alkynyl, C_3- i₂cycloalkyl, aryl, or arylC_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or N0_2; subject to the proviso that when R₃ Js H, the ring system is 1-benzothiophene, R₁ is C(O)OCH₃, and X is -OCH₂-, then R₂ is not C(O)OCH₃; when R₃ is H, the ring system is 1-benzothiophene, R₁ is C(O)OH, and X is — OCH₂-, then R₂ is not C(O)OH; when R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is — OCH₂ — , then R₂ is not C_1-3alkyl ester; when R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is C(O)OC_1-4alkyl, and X is -OCH₂- or -OCH(CH₃)- then R₂ is not CN; when R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is -SCH₂CH₂-, then R₂ is not CN; when R₃is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is — SCH₂ — , then R₂ is not isopropyl ester.

29. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

wherein R-i is C(O)OR₇, 5- to 6-membered heterocycle, H, halogen, CN, or

C(O)NR₇R₈;

R₂ is C(O)ZR₄Or CN; Z is — O— or -NR₅-;

X is — O — Ci_-3alkylene-, — NR₈- C_1-3alkylene-, — S— C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃, N, S, or O; where Y₅ is absent; each R₃ is, independently, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-

₆alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-i₂alkenyI, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylCi_-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^ ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_1-12alkynyl,

C_3-i₂cycloalkyl, aryl, or arylCi_-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

30. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

wherein R₁ is C(O)OC_1-i₂alkyl, 5- to 6-membered heterocycle, H, halogen,

CN, or C(O)NR₇R₈; R₂ is C(O)ZR₄Or CN, wherein R₄ is not methyl;

Z is — O — or — NR₅ — ;

X is — O — C_1-3alkylene-, -NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂- C_1-3alkylene-, — C_1-4alkylene-, — C_2-4aIkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃; where Y₅ is absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, —C(=N— OH)R₄, -NR₄R₅, -NR₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylC^ealkyl, 5- to 8-membered heterocycle, heterocyclicC^ ₆alkyl, aryl, arylC_1-6alkyl, arylC₂.₆alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₉R₉, — NR₇C(O)OR₉, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_2-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

31. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

wherein R₁ is C(O)OH, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈;

R₂ is C(O)ZR₄ or CN, where R₄ is not H;

Z is — O— or— NR₅- ; X is — O— C_1-3alkylene-, — NR₈- C_1-3alkylene-, — S— C_1-3alkylene-, — SO—

C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C^alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃; where Y₅ is absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, —

C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C₂_i₂alkenyl, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^

₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, or -S(O)₂NR₇R₈; each R₇, R₈, and Rg is, independently, H, C^alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-2alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

32. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

wherein R₁ is C(O)OH, C(O)OC_1-2alkyl, C(O)OC_4-12 alkyl, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈;

R₂Js C(O)ZR₄; Z is — O— or -NR₅-;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene~, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄ is, independently, CR₃, N, S, or O; where Y₅ is absent, and where at least one Y₁, Y₂, Y₃, and Y₄ is N; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅₁ -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NS(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_halky!, C_2-12alkenyl, C_2-12alkynyl, C_3-8cycloalkyl,

5- to 8-membered heterocycle, heterocyclicC-i. ₆alkyl, aryl, arylC_1-6alkyl, aryIC_2-6alkenyl, or arylC₂.₆alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH₁ NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, Ci_-12alkyl, C_1-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC-_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

33. The pharmaceutical composition of claim 2, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

wherein R₁ is C(O)OH, C(O)OC_5-12alkyl, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈; R₂ is C(O)ZR₄Or CN; Z is — O— or -NR₅-; X is — O— C_1-3alkylene-, — NR₈- C_1-3alkylene-, — S— C_1-3alkylene-, — SO—

C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O; where one or two Of Y₁, Y₂, Y₃, Y₄, and Y₅ can be absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-i₂alkenyl, C_2-i₂alkynyl,

C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^ ₆alkyl, aryl, arylCi_-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, Ci_-12alkyl, C_2-i₂alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

34. The pharmaceutical composition of claim 2, wherein the compound has the structure of formula (IV), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (IV) being:

(IV)

wherein:

A is defined as -H or -NHC(= O)(CH₂)_nH, where n = 1 to 18; and

B is defined as -H or -(CH₂J_nH, where n = 1 to 18.

35. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for administration to the lungs.

36. The pharmaceutical composition of claim 35, wherein the compound is an inhibitor of PTP1 B enzymatic activity.

37. The pharmaceutical composition of claim 35, wherein administration of the compound to the lungs reduces PTP1 B activity in the hypothalamus, optionally the arcuate nucleus of the hypothalamus.

38. The pharmaceutical composition of claim 35, wherein the composition comprises liquid droplets.

39. The pharmaceutical composition of claim 35, wherein the composition comprises dry powder particles.

40. The pharmaceutical composition of claim 38 or claim 39, wherein the droplets or particles have a tap density of less than 0.4 g/cm³.

41. The pharmaceutical composition of claim 38 or claim 39, wherein the droplets or particles have a mass median geometric diameter of less than 5 microns.

42. The pharmaceutical composition of claim 39, wherein the particles have a mass median geometric diameter of greater than 5 microns.

43. The pharmaceutical composition of claim 38 or claim 39, wherein the droplets or particles have a mass median aerodynamic diameter of 1 to 5 microns.

44. The pharmaceutical composition of claim 35, wherein the composition comprises an inhibitory nucleic acid selected from the group consisting of an antisense RNA, an interfering RNA (RNAi), an aptamer, and a ribozyme.

45. The pharmaceutical composition of claim 35, wherein the composition comprises a nucleic acid selected from the group consisting of a nucleic acid that encodes an antisense RNA, a nucleic acid that encodes an RNAi, a nucleic acid that encodes an aptamer, and a nucleic acid that encodes a ribozyme.

46. The pharmaceutical composition of claim 35, wherein the compound comprises a non-hydrolysable phosphotyrosine mimetic containing peptide, a difluoromethylene phosphonate, a 2-carbomethoxybenzoid acid, a 2- oxalylaminobenzoic acid, a lipophilic compound or a peptidomimetic.

47. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (I) being:

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆; R₂ is R₅; X is — O — C_r3alkylene-, — NR₈ — Cr₃alkylene-, — S — C_t-₃alkylene-, — SO —

Crsalkylene-, — SO₂ — Crsalkylene-, — C^alkylene-, — C₂-₄alkenylene-, — C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q; Y is absent, — O— , or -NR₆-;

R₃ is H, halogen, CN, CF₃, OCF₃, C_halky!, C_3-4cycloalkyl, Crsalkoxy, or aryl; R₄is A-B-E-D, where A is absent or arylene, heteroarylene, Ci_-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl, each A being optionally substituted with one or more of C₁- ₆alkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q; where any of the alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q; and each A being optionally terminated with one or more arylene, alkylene, or alkenylene;

B is absent Or-NR₅-, -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-, -N(R₉)C(O)-, -N(R₉)C(O)C(R₁₁)(R₁₂)-, -N(R₉)C(O)C(O)- — N(R₉)C(O)N(R₁₀)- -N(R)SO₂-, -N(R₉)SO₂C(R₁₀)(R₁₁)-, —

N(R₉)(R₁₀)C(R₁₁)(R₁₂)- -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)-, — O— , — 0-C(R₁₁)(R₁₂), — O— C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂J-O-, -C(R₁₁)(R₁₂HO- C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)-, -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)- - C(R₁₁)(R₁₂)S-, -C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)- or -C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-; E is absent or C₃-₁₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene,

C_ri2alkylene, C₂-₁₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more Ci_-3alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂; D is one or more H, halogen, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, or -S(O)_nR₇, where n is 0, 1 , or 2; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-i₂alkenyl, C_2-i₂alkynyl, C_3-i₂cycloalkyl, C_1-12alkoxyC_1-12alkyl, cycloalkylC_r6alkyl, 3- to 8-membered heterocycyl, heterocycylCi-₆alkyl, aryl, arylC_r6 alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl, where each R₅, R₆, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉Ri₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁-NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂;

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆; and each R₉, R₁₀, Rn, Ri₂, R₁₃and R₁₄ is, independently, H, Ci_₁₂alkyl, C_2-i₂alkenyl,

C_2-12alkynyl, C_3-i₂cycloalkyl, aryl, or aryICrealkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

48. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (I) being:

wherein R₁ is R₅, OR₅, C(O)OR₅, C(O)R₅, or C(O)NR₅R₆;

R₂ Is R₅;

X is — O — C_r3alkylene-, — NR₈- C_r3alkylene-, — S — C-|-₃alkylene-, — SO — Cr₃alkylene-, — SO₂ — Ci-₃alkylene-, — C₁-₄alkylene-, — C₂-₄alkenylene-, — C₂- ₄alkynylene-; wherein any of the alkylene, alkenylene or alkynylene groups is optionally substituted with one or more halogen, oxo, imido, CN, OCF₃, OH, NH₂, NO₂, or Q;

Y is absent, — O — , or — NR₆ — ;

R₃ is H, halogen, CN, CF₃, OCF₃, C_r3 alkyl, C_3-4cycloalkyl, C_r3alkoxy, or aryl; R₄ is A-B-E-D, where A is absent or arylene, heteroarylene, C_1-6alkylene, C_2-6 alkenyldiyl, or C_2-6alkynyl, each A being optionally substituted with one or more of C₁- βalkyl, C₂-₆alkenyl, C₂-₆alkynyl, halogen, CN, OCF₃, OH, NH₂, CHO, NO₂, or Q; where any of the alkyl, alkenyl or alkynyl is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, or Q; and each A being optionally terminated with one or more arylene, alkylene, or alkenylene; B is absent or -NR₅- -NR₇-, -N(R₅)CH₂-, -N(R₇)CH₂-, -N(R₉)-,

-N(R₉)C(O)- -N(R₉)C(O)C(R₁₁)(R₁₂)-, -N(R₉)C(O)C(O)-, - N(R₉)C(O)N(R₁₀)- -N(R)SO₂-, -N(R₉)SO₂C(R₁₀)(Ri₁)- — N(R₉)(R₁₀)C(R₁₁)(R₁₂)-, -N(R₉)C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)-, -0-, -0-C(R₁₁)(R₁₂), — O— C(R₁₁)(R₁₂)C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂J-O- — C(R₁₁)(R₁₂)- O— C(R₁₃)(R₁₄)- -C(R₁₁)(R₁₂)N(R₉)- -C(R₁₁)(R₁₂)N(R₉)C(R₁₃)(R₁₄)-, -

C(R₁₁)(R₁₂)S-, -C(R₁₁)(R₁₂)SC(R₁₃)(R₁₄)- or -C(R₁₁)(R₁₂)SO₂C(R₁₃)(R₁₄)-;

E is absent or C₃-i₂cycloalkylene, 3-to 12-membered heterocycdiyl, arylene, Cr-^alkylene, C₂-₁₂alkenylene, or C₂-₁₂alkynylene, where each E is optionally substituted with one or more C_1-3alkyl, C_1-3alkoxy, halogen, CN, OH, NH₂, or NO₂; D is one or more H, halogen, OH, NH₂, CHO, CN, NO₂, CF₃, or Q; each Q, independently, is -R₅, -R₇, -OR₅, -OR₇, -NR₅R₆, -NR₅R₇, — N⁺R₅R₆R₈, S(O)_nR₅, or -S(O)_nR₇, where n is 0, 1 , or 2; subject to the proviso that when A, B, and E are absent, R-, is C(O)OH or C(O)OCH₃, R₂ is H, and R₃ is H or chlorine, D is not H or chlorine; and when A, B, and E are absent, R₁ is C(O)OH or C(O)OCH₃, R₂ is H, and R₃ is H or bromine, D is not H or bromine; each R₅, R₆, and R₈, independently, is H, C_1-12alkyl, C_2-12alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, C_1-12alkoxyC_1-12alkyl, cycloalkylCrealkyl, 3- to 8-membered heterocycyl, heterocycylCrβalkyl, aryl, arylCpe alkyl, arylC₂-₆ alkenyl, or arylC₂-₆ alkynyl, where each R₅, R₆, and R₈ is optionally substituted with one or more R₉, — OR₉, -OC(O)OR₉, -C(O)R₉, -C(O)OR₉, -C(O)NR₉R₁₀, -SR₉, -S(O)R₉, — S(O)₂R₉, -NR₉R₁₀, -N⁺R₉R₁₀R₁₁-NR₉C(O)R₁₀, -NC(O)NR₉R₁₀, -NR₉S(O)₂R₁₀, oxo, halogen, CN, OCF₃, CF₃, OH, or NO₂;

R₇ is -C(O)R₅, -C(O)OR₅, -C(O)NR₅R₆, -S(O)₂R₅, -S(O)R₅, or — S(O)₂NR₅R₆; and each R₉, R₁₀, R₁₁, R₁₂, R₁₃and R₁₄ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl; where any of the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, or arylalkyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

49. The pharmaceutical composition of claim 47, wherein the compound has a structure of formula (II), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (II) being:

(II)

50. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

R₂ Js C(O)ZR₄Or CN;

Z is — O— or -NR₅-;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene~, — SO₂- C_1-3alkylene-, — C^alkylene-, — C₂-₄alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂,

O₂, R₄, or Q; each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O; where one or two Of Y₁, Y₂, Y₃, Y₄, and Y₅ can be absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, —

NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_halky!, C_2-12alkenyl, C_2-12alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^

₆alkyl, aryl, arylCi_-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₉, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_1-12alkenyl, C_1-12alkynyl, C_3-12cycloalkyl, aryl, or arylC^alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

51. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

R₂ is C(O)ZR₄Or CN; Z is — O — or — NR₅ — ; X is — O — C_1-3alkylene-, -NR₈ — Ci_-3alkylene-, — S — C^alkylene-, — SO —

C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C^alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂,

NO₂, R₄, or Q; each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O; where one or two of Y₁ , Y₂, Y₃, Y₄, and Y₅ can be absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, —

₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₉, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_1-12alkenyl, C_1-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂; subject to the proviso that when R₃ is H, the ring system is 1-benzothiophene, R₁ is C(O)OCH₃, and X is -OCH₂-, then R₂ is not C(O)OCH₃; when R₃ is H, the ring system is 1-benzothiophene, R₁ is C(O)OH, and X is — OCH₂-, then R₂ is not C(O)OH; when R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is — OCH₂ — , then R₂ is not C_1-3alkyl ester; when R₃ is H, the ring system is thieno[2,3-b]pyridine, R-i is C^OC^alkyl, and X is -OCH₂- or— OCH(CH₃)-, then R₂ is not CN; when R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is -SCH₂CH₂-, then R₂ is not CN; when R₃ is H, the ring system is thieno[2,3-b]pyridine, R₁ is isopropyl ester, and X is — SCH₂ — , then R₂ is not isopropyl ester.

52. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

R₂Js C(O)ZR₄Or CN; Z is — O— or -NR₅-; X is — O— C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO —

C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenyIene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃, N, S, or O; where Y₅ is absent; each R₃ is, independently, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2- ₆alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, Ci.₁₆alkyl, C_2-12alkenyl, C_2-12alkynyl,

C_3-8cycloalkyl, cycloaIkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC-i. ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-i₂alkenyl, C_1-12alkynyl, C_3-12cycIoalkyl, aryl, or arylC_1-12alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

53. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

wherein R₁ is C(O)OC_1-12alkyl, 5- to 6-membered heterocycle, H, halogen,

CN, or C(O)NR₇R₈;

R₂is C(O)ZR₄Or CN, wherein R₄ is not methyl; Z is — O— or -NR₅-;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN= CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃; where Y₅ is absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl,

C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -NR₅R₆, -NR₄C(O)R₅, —

NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C_2-t2alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclic^. ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, OXO, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₉R₉, — NR₇C(O)OR₉, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, or -S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC_2-i₂alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

54. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

R₂ is C(O)ZR₄Or CN, where R₄Is not H; Z is — O— or — NR₅- ;

X is — O — C_1-3alkylene-, — NR₈ — C_1-3alkylene~, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄, is, independently, CR₃; where Y₅ is absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-i₂alkenyl, C_2-i₂alkynyl, C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicd. ₆alkyl, aryl, arylC_1-6alkyl, arylC₂-₆alkenyi, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-i₂alkenyl, C_2-12alkynyl, C_3-i₂cycloalkyl, aryl, or arylC_1-2alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

55. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being: (III)

R₂Js C(O)ZR₄; Z is — O— or -NR₅-;

X

— NR₈- C_1-3alkylene-, — S — C_1-3alkylene-, — SO — C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C_2-4alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, and Y₄ is, independently, CR₃, N, S, or O; where Y₅ is absent, and where at least one Y₁, Y₂, Y₃, and Y₄ is N; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NS(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, C_1-16alkyl, C_2-12alkenyl, C_2-i₂alkynyl,

C_3-8cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC^ ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_1-12alkenyl, C_2-i₂alkynyl, C_3-12cycloalkyl, aryl, or arylC-i_₁₂alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

56. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (III), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (III) being:

(III)

wherein R-i is C(O)OH, C(O)OC_5-12alkyl, 5- to 6-membered heterocycle, H, halogen, CN, or C(O)NR₇R₈; R₂is C(O)ZR₄or CN; Z is — O— or -NR₅-; X is — O — C_1-3alkylene-, -NR₈ — C_1-3alkylene-, — S— Ci_₃alkylene-, — SO —

C_1-3alkylene-, — SO₂ — C_1-3alkylene-, — C_1-4alkylene-, — C^alkenylene-, — C_2- ₄alkynylene-; where any of the alkylene, alkenylene and alkynylene groups is optionally substituted with one or more halogen, oxo, HN=, CN, OCF₃, OH, NH₂, NO₂, R₄, or Q; each Y₁, Y₂, Y₃, Y₄, and Y₅ is, independently, CR₃, N, S, or O; where one or two of Y₁, Y₂, Y₃, Y₄, and Y₅ can be absent; each R₃ is, independently, H, aryl, 5- to 8-membered heterocyclyl, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, CN, OCF₃, OH, NH₂, NO₂, or Q; where any of the aryl, heterocyclic, alkyl, alkenyl or alkynyl groups is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, NO₂, N₃, R₄, or Q; each Q is, independently, -OC(O)NR₄R₅, -OR₄, -OC(O)R₄, -COOR₄, — C(O)NR₄R₅, -C(O)R₄, — C(=N— OH)R₄, -NR₄R₅, -N⁺R₄R₅R₆, -NR₄C(O)R₅, — NR₄C(O)NR₅R₆, -NR₄C(O)OR₅, -NR₄S(O)₂R₅, -SR₄, -S(O)R₄, -S(O)₂R₄, or — S(O)₂NR₄R₅; each R₄, R₅, and R₆ is, independently, H, Ci.i₆alkyl, C_2-12alkenyl, C_2-12alkynyl, C₃.₈cycloalkyl, cycloalkylC_1-6alkyl, 5- to 8-membered heterocycle, heterocyclicC-i. ₆alkyl, aryl, arylC_1-6alkyl, arylC_2-6alkenyl, or arylC_2-6alkynyl; where each R₄, R₅, and R₆ is optionally substituted with one or more C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, halogen, oxo, CN₁ OCF₃, OH, NH₂, NO₂, N₃, -OC(O)NR₇R₈, -OR₇, -OC(O)R₇, -COOR₇, -C(O)NR₇R₈, -C(O)R₇, -NR₇R₈, -N⁺R₇R₈R₉, -NR₇C(O)R₈, -NR₇C(O)NR₈R₉, — NR₇C(O)OR₈, -NR₇S(O)₂R₈, -SR₇, -S(O)R₇, -S(O)₂R₇, Or-S(O)₂NR₇R₈; each R₇, R₈, and R₉ is, independently, H, C_1-12alkyl, C_2-12alkenyl, C_2-12alkynyl, C_3-12cycloalkyl, aryl, or arylC^alkyl; where each R₇, R₈, and R₉ is optionally substituted with one or more halogen, oxo, CN, OCF₃, OH, NH₂, or NO₂.

57. The pharmaceutical composition of claim 35, wherein the compound has a structure of formula (IV), or a pharmaceutically acceptable salt or prodrug thereof, the structure of formula (IV) being:

(IV)

wherein:

A is defined as -H or -NHC(= O)(CH₂)_nH, where n = 1 to 18; and

B is defined as -H or -(CH₂)_nH, where n = 1 to 18.

58. A method of reducing PTP1 B activity in the hypothalamus of a mammalian subject, the method comprising intranasally administering to the upper third of the nasal cavity of the mammalian subject an effective amount of a pharmaceutical composition according to claim 2.

59. The method of claim 58, wherein PTP1B activity is inhibited in the arcuate nucleus of the hypothalamus.

60. A method of treating diabetes mellitus in a mammalian subject, the method comprising intranasally administering to the upper third of the nasal cavity of the mammalian subject an effective amount of a pharmaceutical composition according to claim 2.

61. A method of treating metabolic syndrome in a mammalian subject, the method comprising intranasally administering to the upper third of the nasal cavity of the mammalian subject an effective amount of a pharmaceutical composition according to claim 2.

62. A method of reducing peripheral blood glucose concentrations in a mammalian subject, the method comprising intranasally administering to the upper third of the nasal cavity of the mammalian subject an effective amount of a pharmaceutical composition according to claim 2.

63. A method of reducing glucose production in a mammalian subject, the method comprising intranasally administering to the upper third of the nasal cavity of the mammalian subject an effective amount of a pharmaceutical composition according to claim 2.

64. A method of reducing food intake in a mammalian subject, the method comprising intranasally administering to the upper third of the nasal cavity of the mammalian subject an effective amount of a pharmaceutical composition according to claim 2.

65. A method of treating obesity in a mammalian subject, the method comprising intranasally administering to the upper third of the nasal cavity of the mammalian subject an effective amount of a pharmaceutical composition according to claim 2.

66. The method of any of claims 58-65, wherein the subject is a human subject.

67. The method of any of claims 58-65, wherein the subject is an animal model of diabetes mellitus, metabolic syndrome and/or obesity.

68. The method of any of claims 58-66, wherein the subject has diabetes mellitus.

69. The method of any of claims 58-66, wherein the subject has metabolic syndrome.

70. The method of any of claims 58-66, wherein the subject is at least 20% over normal body weight.

71. The method of any of claims 58-70, wherein the pharmaceutical composition is a nasal spray.

72. A method of reducing PTP1 B activity in the hypothalamus of a mammalian subject, the method comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to claim 35.

73. The method of claim 72, wherein PTP1 B activity is reduced in the arcuate nucleus of the hypothalamus.

74. A method of treating diabetes mellitus in a mammalian subject, the method comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to claim 35.

75. A method of treating metabolic syndrome in a mammalian subject, the method comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to claim 35.

76. A method of reducing peripheral blood glucose levels in a mammalian subject, the method comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to claim 35.

77. A method of reducing glucose production in a mammalian subject, the method comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to claim 35.

78. A method of reducing food intake in a mammalian subject, the method comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to claim 35.

79. A method of treating obesity in a mammalian subject, the method comprising pulmonary administration to the mammalian subject of an effective amount of a pharmaceutical composition according to claim 35.

80. The method of any of claims 72-79, wherein the composition comprises liquid aerosol droplets and the composition is administered via a nebulizer.

81. The method of any of claims 72-79, wherein the composition comprises liquid aerosol droplets and the composition is administered via a metered dose inhaler.

82. The method of any of claims 72-79, wherein the composition comprises liquid aerosol droplets and the composition is administered via a pressure- driven, ultrasonic or electrostatic aerosol delivery device.

83. The method of any of claims 72-79, wherein the composition comprises dry powder aerosol particles and the composition is administered via a dry powder inhaler.

84. The method of any of claims 72-83, wherein at least 10% of the composition is delivered to the alveolar region.

85. The method of any of claims 72-84, wherein the subject is a human subject.

86. The method of any of claims 72-85, wherein the subject is an animal model of diabetes mellitus, insulin resistance, glucose intolerance, hyperglycemia, metabolic syndrome and/or obesity.

87. The method of any of claims 72-85, wherein the subject has diabetes mellitus.

88. The method of any of claims 72-85, wherein the subject has metabolic syndrome.

89. The method of any of claims 72-88, wherein the subject is at least 20% over normal body weight.

90. The method of any of claims 72-89, wherein the method of pulmonary administration is by oral inhalation.

91. A method of identifying a compound that can be administered to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to reduce protein tyrosine phosphatase 1 B (PTP1 B) activity in the hypothalamus, the method comprising: administering a compound to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung; and evaluating PTP1 B activity in the hypothalamus; wherein a reduction in PTP1 B activity in the hypothalamus as compared with

PTP1 B activity in the absence of administration of the compound indicates that the compound is a compound that can be delivered by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to reduce PTP1 B activity in the hypothalamus.

92. A method of identifying a compound that can be administered to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to reduce glucose production, reduce peripheral blood glucose concentrations and/or to treat hyperglycemia, insulin resistance and/or glucose intolerance, the method comprising: administering a compound to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung; and evaluating protein tyrosine phosphatase 1 B (PTP1 B) activity in the hypothalamus; wherein a reduction in PTP1 B activity in the hypothalamus as compared with PTP1 B activity in the absence of administration of the compound indicates that the compound is a compound that can be delivered by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to reduce glucose production, reduce peripheral blood glucose concentrations and/or to treat hyperglycemia, insulin resistance and/or glucose intolerance.

93. A method of identifying a compound that can be administered to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to treat diabetes, the method comprising: administering a compound to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung; and evaluating protein tyrosine phosphatase 1 B (PTP1 B) activity in the hypothalamus; wherein a reduction in PTP1 B activity in the hypothalamus as compared with PTP1 B activity in the absence of administration of the compound indicates that the compound is a compound that can be delivered by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to treat diabetes.

94. A method of identifying a compound that can be administered to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to treat metabolic syndrome, the method comprising: administering a compound to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung; and evaluating protein tyrosine phosphatase 1 B (PTP1 B) activity in the hypothalamus; wherein a reduction in PTP1 B activity in the hypothalamus as compared with PTP1 B activity in the absence of administration of the compound indicates that the compound is a compound that can be delivered by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to treat metabolic syndrome.

95. A method of identifying a compound that can be administered to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to reduce food intake and/or appetite, the method comprising: administering a compound to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung; and evaluating protein tyrosine phosphatase 1 B (PTP1 B) activity in the hypothalamus; wherein a reduction in PTP1 B activity in the hypothalamus as compared with

PTP1 B activity in the absence of administration of the compound indicates that the compound is a compound that can be delivered by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to reduce food intake and/or appetite.

96. A method of identifying a compound that can be administered to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to treat obesity, the method comprising: administering a compound to a subject by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung; and evaluating protein tyrosine phosphatase 1 B (PTP1 B) activity in the hypothalamus; wherein a reduction in PTP1 B activity in the hypothalamus as compared with PTP1B activity in the absence of administration of the compound indicates that the compound is a compound that can be delivered by intranasal delivery to the upper third of the nasal cavity or by pulmonary delivery to the lung to treat obesity.

97. The method of any of claims 91-96, wherein the compound is administered to the subject by intranasal administration.

98. The method of any of claims 91-96, wherein the compound is administered to the subject by pulmonary administration.

99. An intranasal delivery device comprising a pharmaceutical composition of claim 2.

100. A pulmonary delivery device comprising a pharmaceutical composition of claim 35.