WO2009105234A2 - Methods and compositions for the treatment of disorders associated with defects of the cystic fibrosis transmembrane conductance regulator gene or protein - Google Patents

Methods and compositions for the treatment of disorders associated with defects of the cystic fibrosis transmembrane conductance regulator gene or protein Download PDF

Info

Publication number
WO2009105234A2
WO2009105234A2 PCT/US2009/001061 US2009001061W WO2009105234A2 WO 2009105234 A2 WO2009105234 A2 WO 2009105234A2 US 2009001061 W US2009001061 W US 2009001061W WO 2009105234 A2 WO2009105234 A2 WO 2009105234A2
Authority
WO
WIPO (PCT)
Prior art keywords
agents
composition
kit
agent selected
statin
Prior art date
Application number
PCT/US2009/001061
Other languages
French (fr)
Other versions
WO2009105234A3 (en
Inventor
Stephen Lin
Jane Staunton
Jinliang Sui
Original Assignee
Combinatorx, Incorporated
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Combinatorx, Incorporated filed Critical Combinatorx, Incorporated
Publication of WO2009105234A2 publication Critical patent/WO2009105234A2/en
Publication of WO2009105234A3 publication Critical patent/WO2009105234A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • Cystic fibrosis is a lethal, autosomal-recessive genetic disease, affecting approximately 30,000 individuals in the United States.
  • CF is characterized by defective chloride transport, resulting from a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
  • the CFTR gene encodes a linear chloride channel protein in the plasma membrane of certain epithelial cells, where it regulates the flow of chloride ions in response to phosphorylation by a cyclic AMP-dependent kinase.
  • Many mutations of the CFTR protein have been reported, the most common of which is a deletion of a phenylalanine residue ( ⁇ F508 CFTR). Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent CF.
  • CF CFTR fibrosis .
  • the principal clinical manifestation of CF is the resulting respiratory disease, characterized by airway obstruction due to the presence of thick mucus that is difficult to clear from airway passages. This airway mucus contributes to recurrent bacterial infections and impaired respiration, eventually resulting in death.
  • Treatment of CF involves the thinning of mucosal obstructions, treating bacterial infections, using anti-inflammatory compositions to treat lung inflammation, and opening airways with bronchodilators.
  • frequent hospitalization is often required as the disease progresses. Accordingly, improvements are needed for the treatment of CF and other disorders associated with defects of the CFTR gene or protein.
  • the present invention features compositions, methods, and kits for treating or ameliorating disorders associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein (e.g., cystic fibrosis).
  • CFTR cystic fibrosis transmembrane conductance regulator
  • the invention features a composition that includes an agent selected from Table 1. Desirably, the agent is present in an amount that, when administered to a patient, is sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes a first agent selected from Table 1 or 2 and a second, different agent selected from Table 1, 2, or 3. Desirably, the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes active ingredients and excipients, wherein the active ingredients are, for example, a first compound from Table 1 or 2 and a second compound from Table 1, 2, or 3.
  • the invention features a composition that includes a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3.
  • the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein.
  • compositions of the invention may be formulated, for example, for oral administration, systemic administration, or for inhalation.
  • the invention also features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein by administering to a patient an agent selected from Table 1 in an amount sufficient to treat or ameliorate the disorder.
  • the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1 and a second, different agent selected from Table 1, 2, or 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder.
  • the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder.
  • the agents of the methods may be administered substantially simultaneously in amounts that together are sufficient to treat or ameliorate the disorder.
  • the agents may be administered within 1, 2, 4, 6, 12, or 24 hours of each other, within 7 days of each other, within 14 days of each other, or within 28 days of each other.
  • the agents may be administered by any appropriate route, e.g., by oral administration, systemic administration, or inhalation.
  • the invention also features a kit that includes at least one agent selected from Table 1 and instructions for administering the agent to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with a defect in the CFTR gene or protein e.g., cystic fibrosis
  • the invention features a kit that includes a first agent selected from Table 1, a second, different agent selected from Table 1, 2, or 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with a defect in the CFTR gene or protein e.g., cystic fibrosis
  • the invention features a kit that includes a first agent selected from Table 1, a second agent selected from Table 2, a third agent selected from Table 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with a defect in the CFTR gene or protein e.g., cystic fibrosis.
  • Combinations of the compounds described herein may be used as therapeutic agents in the compositions, methods, and kits of the present invention.
  • Such combinations include, e.g., Corr-4a and HC toxin; Corr-4a and valproic acid; Corr-4a and suberoylanilide hydroxamic acid; atorvastatin calcium and HC toxin; prednisolone and suberoylanilide hydroxamic acid; quinestrol and suberoylanilide hydroxamic acid; chlormadinone acetate and Corr-4a; 2-APB and histone deacetylase inhibitor III; staurosporine and suberoylanilide hydroxamic acid; BAY 60-7550 and suberoylanilide hydroxamic acid; drotaverine hydrochloride and suberoylanilide hydroxamic acid; BAY 60-7550 and CF-C3; CF-C6 and gliquidone; Corr-4a and LY
  • an amount sufficient is meant the amount of a compound, alone or in combination with another compound or therapeutic regimen, required to treat or ameliorate a disorder, such as cystic fibrosis, in a clinically relevant manner.
  • a sufficient amount of an active compound used to practice the present invention for therapeutic treatment of, e.g., cystic fibrosis varies depending upon the manner of administration, age, and general health of the patient.
  • the prescribers will decide the appropriate amount and dosage regimen.
  • an effective amount may be an amount of compound in the combination of the invention that is safe and efficacious in the treatment of a patient having a disorder, such as cystic fibrosis, over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug Administration).
  • Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally-occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof.
  • Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures. Compounds useful in the invention may also be isotopically labeled compounds.
  • Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 Cl).
  • Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically- labeled reagent in place of a non-isotopically-labeled reagent.
  • disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein is meant any disorder resulting from a mutation of the CFTR gene or protein (e.g., a deletion of F508, a G542X mutation, a G551D mutation, a N1303K mutation, or a W1282X mutation).
  • exemplary disorders include cystic fibrosis, the congenital absence of the vas deferens, and some forms of pancreatitis.
  • a “high dosage” is meant at least 5% more (e.g., at least 10%, 20%, 30%, 40%, 50%, 100%, 150%, 200%, or 300%) than the highest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any disease or condition.
  • a high dosage of an agent that treats or prevents cystic fibrosis and that is formulated for intravenous administration may differ from a high dosage of the same agent formulated for oral administration.
  • a “low dosage” is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for the treatment of any disease or condition.
  • patient is meant any animal, e.g., a mammal (e.g., a human).
  • compositions, methods, and kits of the invention include, e.g., horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds.
  • a patient who is being treated for a disorder associated with a CFTR defect is one who has been diagnosed by a medical practitioner as having such a condition. Diagnosis may be performed by any suitable means, such as those described herein.
  • salts 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, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • Representative acid addition salts include, e.g., acetate, ascorbate, aspartate, benzoate, citrate, digluconate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, lactate, malate, maleate, malonate, mesylate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, valerate salts, and the like.
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
  • sustained release or “controlled release” is meant that the therapeutically active component is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the component are maintained over an extended period of time ranging from, e.g., about 12 to about 24 hours, thus, providing, for example, a 12-hour or a 24-hour dosage form.
  • systemic administration is meant any non-dermal route of administration, and specifically excludes topical and transdermal routes of administration.
  • therapeutic agent is meant any agent that produces a healing, curative, stabilizing, or ameliorative effect.
  • treating or ameliorating is meant ameliorating a condition or symptoms of the condition (e.g., cystic fibrosis) before or after its onset.
  • amelioration or degree of treatment is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
  • Exemplary therapeutic agents used for the treatment of any patient that has been diagnosed with a disorder associated with defects of a CFTR gene or protein are listed in Tables 1, 2, and 3.
  • Mibefradil e.g., dihydrochloride hydrate salt
  • Neomycin e.g., trisulfate salt hydrate
  • Protopine e.g., hydrochloride salt
  • Thioridazine e.g., hydrochloride salt
  • Figure 1 is a representative graph showing the fluorescence of FRT cells ( ⁇ F508; eYFP) incubated with DMSO alone (FL DMS o) > with forskolin alone (FL FSK X or with forskolin and a candidate compound (FL FSK+GEN ) before and after contact with an iodide solution.
  • CFTR cystic fibrosis transmembrane conductance regulator
  • cystic fibrosis for example, such administration may decrease mucus production, decrease sputum viscosity, decrease blood pressure of the lung, reduce inflammation of the sinuses, lung, and pancreas, decrease thickened secretions that block bile ducts, control CF-related diabetes, or maximize organ function.
  • compositions, methods, and kits of the present invention are useful for treating any patient that has been diagnosed with a disorder associated with defects of the CFTR gene or protein (e.g., cystic fibrosis).
  • a disorder associated with defects of the CFTR gene or protein e.g., cystic fibrosis.
  • patients of the invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
  • CFTR-defect disorders e.g., CF
  • CFTR-defect disorders may be diagnosed and monitored using, for example, sweat (or chloride) tests to measure the amount of chloride in the sweat, which involves stimulating sweat from the patient with a mild electric current. The sweat is collected onto a gauze pad and analyzed. Higher than normal concentrations of chloride may be suggestive of a CFTR-defect disorder.
  • Blood tests may also be performed to test for mutations in the CFTR gene. Chest x-rays, pulmonary function tests (e.g., diagnostic tests that help to measure the lungs' ability to exchange oxygen and carbon dioxide), sputum cultures, stool evaluations (e.g., to measure stool fat absorption), and pancreatic function tests may also be used to diagnosis CFTR-defect disorders. The use of any of the above tests or any other tests known in the art may be used to monitor the efficacy of the present treatment.
  • Chest x-rays pulmonary function tests (e.g., diagnostic tests that help to measure the lungs' ability to exchange oxygen and carbon dioxide), sputum cultures, stool evaluations (e.g., to measure stool fat absorption), and pancreatic function tests may also be used to diagnosis CFTR-defect disorders. The use of any of the above tests or any other tests known in the art may be used to monitor the efficacy of the present treatment.
  • Exemplary therapeutic agents used for the treatment of any patient that has been diagnosed with a disorder associated with defects of a CFTR gene or protein are listed in Tables 1, 2, and 3.
  • Preferred agents include, e.g., statins, steroids, flavonoids, dihydropyridines, HDAC inhibitors, sulfonylureas, PPAR agonists, estrogen/estradiol receptor modulators, PDE inhibitors and adenosine receptor modulators, kinase inhibitors, NSAIDs and leukotriene antagonists, proton pump inhibitors, channel modulators, and receptor modulators.
  • Statins may be used as therapeutic agents in the compositions, methods, and kits of the invention, alone or in combination with additional agents.
  • Statins of the invention include atorvastatin; cerivastatin; fluvastatin; lovastatin; rosuvastatin; acitemate; amlodipine/atorvastatin; BAY102987; BAY
  • SC371 1 1 SC45355; simvastatin; SQ33600; SR12813; SR45023A; U20685; and U88156.
  • statins and statin derivatives are described, for example, in U.S. Patent Nos. 2,956,066, 3,288,826, 4,397,786, 4,803,292, 6,689,590, 7,199,102, and 7,297,808, hereby incorporated by reference. Additional statins and analogs thereof useful in the methods and compositions of the present invention are described, for example, in U.S. Patent Nos.
  • Steroids may be used as therapeutic agents in the compositions, methods, and kits of the invention, alone or in combination with additional agents.
  • Steroids include, e.g., sex hormones and corticosteroids (e.g., glucocorticoids and mineralcorticoids).
  • steroids of the invention include corticosterone; fluocinonide; fluprednisolone; rimexolone; triamcinolone; 11 -alpha, 17-alpha,21-trihydroxypregn-4-ene-3,20-dione; 11- beta, 16-alpha, 17,21 -tetrahydroxypregn-4-ene-3,20-dione; 1 1 -beta, 16- alpha, 17,2 l-tetrahydroxypregn-l,4-diene-3,20-dione; 1 l-beta,17-alpha,21- trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione; 11-dehydrocorticosterone; 1 1-deoxycortisol; 11 -hydroxy- l,4-androstadiene-3, 17-dione; 1 1- ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17- dihydroxypro
  • Cortisol Cortisol; Cortisol acetate; Cortisol butyrate; Cortisol cypionate; Cortisol octanoate; Cortisol sodium phosphate; Cortisol sodium succinate; Cortisol valerate; cortisone; cortisone acetate; cortodoxone; daturaolone; deflazacort,
  • compositions, methods, and kits of the invention include, e.g., A-348441 ; adrenal cortex extract; alsactide; amebucort; amelometasone;
  • Lipocort Lipocort; locicortone; meclorisone; naflocort; NCX-1015; NCX- 1020; NCX-1022; nicocortonide; NIK-236; NS-126; Org-2766; Org-6632; P 16CM, propylmesterolone; RGH-1113; rofleponide; rofleponide palmitate; RPR-106541 ; RU-26559; Sch-19457; T25; TBI-PAB; ticabesone propionate; tifluadom; timobesone; TSC-5; and ZK-73634.
  • Standard recommended dosages for corticosteroids are provided, e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians' Desk Reference 2003 (57 th Ed. Medical Economics Staff et al., Medical Economics Co., 2002), hereby incorporated by reference.
  • the synthesis of steroids and steroid derivatives is described, for example, in DE 2361120 and in U.S. Patent Nos. 2,760,966, 2,760,975, 3,927,046, 4,102,925, 4,183,864, and 4,267,376, hereby incorporated by reference.
  • Flavonoids may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary flavonoids of the invention include, e.g., apigenin, genistein, isoliquiritigenin, quercetin, or 2-hydroxyflavanone.
  • Additional flavonoids include taxifolin, catechin, epicatechin, eriodictyol, naringenin, troxerutin, chrysin, tangeretin, luteolin, epigallocatechin and epigallocatechin gallate, fisetin, kaempferol, galangin, gallocatechin, and epicatechin gallate.
  • flavonoids and flavonoid derivatives are described, for example, in U.S. Patent Nos. 4,617,293, 5,756,538, 6,004,998, 6,028,088, 6,087,385, and 7,138,429, hereby incorporated by reference.
  • Dihydropyridines may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary dihydropyridines of the invention are felodipine, isradipine, nimodipine, or nisoldipine.
  • Additional dihydropyridines include, e.g., nicardipine, nifedipine nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, benidipine, azelnidipine, and lercanidipine.
  • dihydropyridines and dihydropyridine derivatives are described, for example, in DE 2904552, EP 63365, EP 106275, and in U.S. Patent Nos. 4,044,141, 4,179,570, 4,220,649, 4,448,964, 5,492,923, 5,661,157, 5,712,296, 6,239, 155, and 7,074,931, hereby incorporated by reference.
  • Histone Deacetylase Inhibitors and Analogs or Derivatives Thereof Histone deacetylase (HDAC) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Histone deacetylase (HDAC) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary HDAC inhibitors of the invention are suberoylanilide hydroxamic acid (SAHA) and derivatives thereof (e.g., SAHA)
  • peptidic compounds including certain tripeptides, cyclic tetrapeptides, cyclic disulfides, and ketone derivatives thereof (e.g., HC toxin, chlamydocin, apicidins, trapoxin A, trapoxin B, depudecin, WF-3161, WF27082 (U.S. Patent No.
  • HDAC inhibitors are described in Saito, et al. (Proc. Natl. Acad. ScL USA 96:4592-4597, 1999), Furamai et al. ⁇ Proc. Natl. Acad. Sci. USA 98:87-92, 2001), Komatsu et al. ⁇ Cancer Res. 61 :4459-4466, 2001), Su et al. ⁇ Cancer Res. 60:3137-3142, 2000), Suzuki et al. ⁇ J. Med. Chem. 42:3001- 3003, 1999), in U.S. Patent Application Publication Nos. 2008/0146623,
  • Sulfonylureas and peroxisome proliferator-activated receptor (PPAR) agonists may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • exemplary sulfonylureas and PPAR agonists are gliquidone; glitazones (e.g., balaglitazone, troglitazone, pioglitazone, ciglitazone, englitazone, rosiglitazone, darglitazone, englitazone, netoglitazone, KRP-297, JTT-501, NC-2100, NIP-223, MCC-555, L-764486, and CS-Ol 1); acetohexamide; chlorpropamide; tolbutamide; tolazamide; glipizide; gliclazide; glibenclamide; glyclopyramide; glimepiride; GI262570; [(S)-2-
  • Estrogen and estradiol receptor modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary estrogen and estradiol receptor modulators are quinestrol and its metabolites (e.g., ethinyl estradiol); megestrol; melengestrol; desmosterol; centchroman; estrogen; progestogen; estradiol; alfatradiol; estriol; droloxifene; raloxifene; lasofoxifene; TSE-424; tamoxifen; idoxifene; LY353381 ; LYl 17081 ; toremifene; fulvestrant; 4-[7-(2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4-[2-( 1 -piperidiny l)ethoxy]phenyl]-2H- 1 - benzopyran-3-yl]-phenyl-2,2-
  • Phosphodiesterase (PDE) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Type I PDE inhibitors include (3- ⁇ ,16- ⁇ )-eburnamenine-14-carboxylic acid ethyl ester (Vinpocetine); l,8-methoxymethyl-3-isobutyl-l-methylxantine (MIMX); l-carboxy-23A4Mb ⁇ 6,6a,6bJ ⁇ 8a,8b,9,10, 10a,14, 16, 17,17a,17b,18, 19,19a, 19b, 20,21,21a,21b,22,23,23a-dotriacontahydro-14- hydroxy-8a, 1 Oa-bis(hydroxymethyl)- 14-(3-methoxy-3-oxopropyl)- 1 ,4,4a, 6,6a,17b,19b,21b-octamethyl beta-D-glucopyranos
  • Type II PDE inhibitors include erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA); 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methyl-2-((2,4,6- trimethylphenyl)imino)-4H-pyrimido(6, 1 -a)isoquinolin-4-one (trequinsin); ND7001 ; and BAY 60-7550.
  • EHNA erythro-9-(2-hydroxy-3-nonyl)adenine
  • trequinsin 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methyl-2-((2,4,6- trimethylphenyl)imino)-4H-pyrimido(6, 1 -a)isoquinolin-4-one
  • ND7001 ND7001
  • BAY 60-7550 BAY 60-7550.
  • Other Type II PDE inhibitors are described in U.S. Patent Application Publication No. 2003/0176316.
  • Type III PDE inhibitors include 3-isobutyl-l-methylxanthine (IBMX); 6-dihydro-2-methyl-6-oxo-3,4'-bipyridine)-5-carbonitrile (milrinone); zardaverine; and N-cyclohexyl-4-(( 1 ,2-dihydro-2-oxo-6-quinolinyl)oxy)-N- methyl-butanamide (cilostamide).
  • IBMX 3-isobutyl-l-methylxanthine
  • zardaverine zardaverine
  • Type III PDE inhibitors are described in EP 0653426, EP 0294647, EP 0357788, EP 0220044, EP 0326307, EP 0207500, EP 0406958, EP 0150937, EP 0075463, EP 0272914, and EP 01 12987, in U.S. Patent Nos. 4,963,561, 5,141,931, 6,897,229, and 6,156,753, in U.S. Patent Application Publication Nos. 2003/0158133, 2004/0097593, 2006/0030611, and 2006/0025463, in PCT Publication Nos.
  • Type IV PDE inhibitors include 4-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidone (rolipram); roflumilast; 4-(3-butoxy-4- methoxybenzyl)-2-imidazolidinone (Ro20-1724); and etazolate.
  • Other Type IV PDE inhibitors are described in U.S. Patent Nos.
  • Type V PDE inhibitors include sildenafil; vardenafil; and tadalafil.
  • Other Type V PDE inhibitors are described in U.S. Patent Nos. 6,992, 192, 6,984,641, 6,960,587, 6,943, 166, 6,878,711, and 6,869,950, and in U.S. Patent Application Publication Nos. 2003/0144296, 2003/0171384, 2004/0029891, 2004/0038996, 2004/0186046, 2004/0259792, 2004/0087561, 2005/0054660, 2005/0042177, 2005/0245544, and 2006/0009481.
  • Type VI PDE inhibitors include those described in U.S. Patent Application Publication Nos. 2004/0259792, 2004/0248957, 2004/0242673, and 2004/0259880.
  • Type VII PDE inhibitor includes BRL-50481.
  • Other Type VII PDE inhibitors include those described in U.S. Patent Nos.
  • Tofisopam is an exemplary Type X PDE inhibitor. Tofisopam analogs are described in HU 155572, GB 1202579, and in U.S. Patent No. 3,736,315. Kinase Inhibitors and Analogs and Derivatives Thereof
  • Kinase inhibitors e.g., tyrosine, GSK3, p38, CAMKK, Akt, Cdk,
  • EGFR, JNK, MAP, MEK, MLCK, PB, or VEGFR kinase inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • exemplary kinase inhibitors are bevacizumab; BIBW 2992; cetuximab; trastuzumab; sunitinib; erlotinib; neratinib; nilotinib; lapatinib; panitumumab; vandetinib; E7080; ranibizumab; pegaptanib; sorafenib; imatinib; motesanib; leflunomide; ZDl 839; erlotinib; canertinib; squalamine; SU 4312; SU 5416; ZD4190; vatalanib; PKI-166; GW2016; EKB-509; trastuzumab; EKB-569;
  • Exemplary kinase inhibitors are those described in DE 2347682 and EP
  • Non-steroidal anti-inflammatory drugs which include, e.g., COX-2 inhibitors and sulphonanilides, may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • NSAIDs are detoprofen; diclofenac; diflunisal; etodolac; etoricoxib; fenoprofen; flunixin meglumine; flurbiprofen; ibuprofen; indomethacin; ketoprofen; lumiracoxib; meclofenameate; mefenamic acid; meloxicam; nabumeone; naproxen sodium; oxaprozin; parecoxib; piroxicam; sulindac; tolmetin; valdecoxib; celecoxib; rofecoxib; aspirin; choline salicylate; salsalte; acemetacin; alminoprofen; am
  • Leukotriene antagonists may also be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Leukotriene antagonists include zileuton; 5-lipoxygenase;
  • MK-886 FLAP; montelukast; acitazanolast; iralukast; montelukast; zafirlukast; pranlukast; and velukast.
  • Proton pump inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary proton pump inhibitors are omeprazole; lansoprazole; esomeprazole; pantoprazole; and rabeprazole.
  • Channel modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • Exemplary channel modulators are A-53930A; AE-0047;
  • R-(+), and racemic anipamil; 2-APB; AP-1067; aranidipine; atosiban; azelnidipine; barnidipine; BAY K8644; Bay-t-7207; Bay-y-5959; Bay-z-4406;
  • BBR-2160 belfosdil; BIII-890-CL; bisaramil; BMS-181 102; BMS-188107;
  • BMY-4301 1 BMY-4301 1 ; BRL-32872; buflomedil; capsaicin derivatives (e.g., TRPV); CD- 349; CD-832; CERM- 12816; CGP-28932; cilnidipine; dentiazem; clevidipine;
  • SIB- 1281 siratiazem; SKFA-45675; SKF-96365; SKT-M-26; SL-34.0829; SL-
  • Receptor modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents.
  • exemplary receptor modulators are otilonium bromide, drotaverine, dextromethorphan, and hydrobromide (opioid receptor modulators); promethazine (histamine receptor modulator); securinine and diazepam (GABA receptor modulators); and nebivolol and phenoxylbenzamine (adrenergic receptor modulators). Additional receptor modulators are described in BE 621917 and in U.S.
  • Fludarabine analogs are described in U.S. Patent No. 4,210,745 and U.S. Patent No. 4,357,324. Fludrocortisone analogs are described in U.S. Patent No. 2,957,013, GB 792224, and U.S. Patent No. 2,852,51 1. Flunisolide analogs are described in GB 933867, U.S. Patent No. 3,124,571, and U.S. Patent No. 3,126,375. Fluocinolone acetonide analogs are described in U.S. Patent No. 3,014,938 and U.S. Patent No. 3, 126,375. Fluocinonide analogs are described in GB 916996, U.S. Patent No.
  • Triflupromazine analogs are described in GB 813861.
  • Albendazole analogs are described in U.S. Patent No. 3,915,986.
  • Amitriptyline analogs are described in BE 584061, GB 858187, GB 858188, and U.S. Patent No. 3,205,264.
  • Amoxicillin analogs are described in GB 978178, U.S. Patent No. 3,192,198, DE 1942693, and GB 1241844.
  • Bepridil analogs are described in DE 2310918, U.S. Patent No. 3,962,238, and DE 2802864.
  • Bicalutamide analogs are described in EP 100172 and U.S. Patent No. 4,636,505.
  • Butoconazole analogs are described in U.S. Patent No. 4,078,071. Chlorquinaldol analogs are described in U.S. Patent No. 2,41 1 ,670. Chlorothymol analogs are described in DE 905738. Chlorprothixene analogs are described in GB 829763 and U.S. Patent No. 3,046,283. Clemastine fumarate analogs are described in GB
  • Clomipramine analogs are described in CH 371799 and U.S. Patent No. 3,467,650.
  • Cloperastine analogs are described in GB 670622 and GB 1179945.
  • Clopidogrel analogs are described in EP 99802, U.S. Patent No. 4,529,596, EP 281459, and U.S. Patent No. 4,847,265.
  • Clorofene analogs are described in U.S. Patent No. 1,967,825 and DE 703955.
  • Dienestrol analogs are described in U.S. Patent No. 2,464,203 and U.S. Patent No. 2,465,505.
  • Donepezil analogs are described in EP 296560 and U.S. Patent No. 4,895,841.
  • Doxepin analogs are described in U.S. Patent No. 3,438,981, NL 6407758, BE 641498, and U.S. Patent No. 3,420,851.
  • Ethinyl estradiol analogs are described in DE 702063, GB 516444, U.S. Patent No. 2,243,887, U.S. Patent No. 2,251,939, U.S. Patent No. 2,265,976, and U.S. Patent No. 2,267,257.
  • Ezetimibe analogs are described in WO 95/08532 and U.S. Patent No. 5,767,115.
  • Fenofibrate analogs are described in DE 2250327, DE 2003430, and U.S. Patent No. 4,058,552. Fenticlor analogs are described in DE 568944. Hydroxyzine analogs are described in U.S. Patent No. 2,899,436. Ibudilast analogs are described in DE 2315801 and U.S. Patent No. 3,850,941. Irsogladine analogs are described in DE 2506814 and U.S. Patent No. 3,966,728. Isradipine analogs are described in DE 2949491, U.S. Patent No. 4,466,972, and DE 3320616. Lansoprazole analogs are described in EP 174726 and U.S. Patent No. 4,628,098.
  • Nisoldipine analogs are described in DE 2549568 and U.S. Patent No. 4,154,839. Octyl methoxycinnamate analogs are described in U.S. Patent No. 4,713,473. Permethrin analogs are described in DE 2437882, DE 2544150, and U.S. Patent No. 4,1 13,968. Phenothiazine analogs are described in DE 25150, U.S. Patent No. 2,415,363, U.S. Patent No. 2,887,482, and U.S. Patent No. 3,000,887. Triclabendazole analogs are described in BE 865870 and U.S. Patent No. 4,197,307.
  • Zafirlukast analogs are described in U.S. Patent No. 4,859,692 and EP 199543.
  • Amiloride analogs are described in U.S. Patent No. 3,313,813 and BE 639386.
  • Amiodarone analogs are described in U.S. Patent No. 3,248,401 and FR 1339389.
  • Diltiazem analogs are described in U.S. Patent No. 4,552,695, DE 1805714, DE 3415035, and U.S. Patent No. 3,562,257.
  • Gabapentin analogs are described in U.S. Patent No. 4,024,175 and DE 2460891.
  • Ivermectin analogs are described in U.S. Patent No.
  • Penfluridol analogs are described in U.S. Patent No. 3,575,990 and DE 2040231. Phloretin analogs are described in U.S. Patent No. 2,789,995. Mibefradil analogs are described in U.S. Patent No. 4,808,605 and EP 268148. Letrazole analogs are described in U.S. Patent No. 4,978,672 and EP 236940. Medrysone analogs are described in U.S. Patent Nos. 2,864,837 and 2,968,655. Naltrexone analogs are described in U.S. Patent No. 3,332,950. Phenazopyridine analogs are described in U.S. Patent Nos.
  • Diazepam analogs are described in U.S. Patent Nos. 3,371,085, 3,109,843, 3,136,815, and 3,102,116.
  • Pramipexole analogs are described in U.S. Patent No. 4,886,821 and EP 186087. Rosiglitazone analogs are described in U.S. Patent No. 5,002,953 and EP 306228.
  • Ciclesonide analogs are described in U.S. Patent No. 5,482,934 and DE 4129535.
  • Auranofin analogs are described in U.S. Patent No. 3,635,945 and DE 2051495.
  • Clofoctol analogs are described in U.S. Patent No. 3,830,852. Clotrimazole analogs are described in U.S.
  • Patent No. 4,663,325 and EP 159566 Naftifine analogs are described in U.S. Patent No. 4,282,251, BE 853976, and ES 504432. Naltrexone analogs are described in U.S. Patent No. 3,332,950. Pimozide analogs are described in FR M3695. Rabeprazole analogs are described in U.S. Patent No. 5,045,552 and EP 268956. Tioconazole analogs are described in U.S. Patent No. 4,062,966 and BE 841309. Amprenavir analogs are described in U.S. Patent No. 5,585,397 and WO 94/05639.
  • Celecoxin analogs are described in U.S. Patent No. 5,466,823 and WO 95/15316.
  • Budesonide analogs are described in U.S. Patent No. 3,929,768 and DE 2323215.
  • Diacerein analogs are described in U.S. Patent Nos. 4,244,968 and 4,346,103, as well as DE 271 1493 and JP Kokai 83 225015.
  • Rolipram analogs are described in U.S. Patent No. 4,193,926 and BE 826923.
  • Biothionol analogs are described in DE 583055 and U.S. Patent No. 2,849,494.
  • Epirubicin analogs are described in DE 2510866, BE 898506, GB 2133005, and U.S. Patent No.
  • Trifluoperazine analogs are described in GB 813861 and U.S. Patent No. 2,921,069.
  • Nortriptyline analogs are described in NL 6408512 and U.S. Patent Nos. 3,442,949 and 3,922,305.
  • Tamoxifen analogs are described in BE 637389, BE 678807, and in U.S. Patent Nos. 4,536,516, 6,096,874, 6,576,645, 6,875,775, and 5,807,899.
  • Nebivolol analogs are described in EP 145067 and U.S. Patent No. 4,654,362.
  • Pranlukast analogs are described in EP 173516 and U.S. Patent No. 4,780, 469.
  • Emetine analogs are described in U.S. Patent No. 3, 102,118.
  • Diphenoxylate hydrochloride analogs are described in U.S. Patent No. 2,898,340.
  • Gestodene analogs are described in BE 847090 and U.S. Patent No. 4,081,537.
  • Diazolidinyl urea analogs are described in WO 81/00566 and U.S. Patent No. 4,271,176.
  • Oxymethurea analogs are described in U.S. Patent Nos. 1,863,426 and 2,436,355.
  • Chloramphenicol analogs are described in GB 795131, GB 796901, and in U.S. Patent Nos.
  • Cephapirin analogs are described in ZA 67 07783 and in U.S. Patent Nos. 3,422,100, 3,503,967, and 3,578,661.
  • Dioxybenzone analogs are described in U.S. Patent No. 2,853,521.
  • Efavirenz analogs are described in EP 582455 and U.S. Patent No. 5,519,021.
  • Saperconazole analogs are described in EP 283992 and U.S. Patent No. 4,916,134.
  • Securine analogs are described in GB 1169471 and U.S. Patent No. 3,538,103. Benproperine phosphate analogs are described in GB 914008 and U.S. Patent No. 3,117,059.
  • Epoxomicin analogs are described in EP 411660 and U.S. Patent No. 5,071,957.
  • Fenipentol analogs are described in GB 915815 and U.S. Patent No. 3,084,100.
  • Phenoxybenzamine analogs are described in U.S. Patent No. 2,599,000.
  • Telithromycin analogs are described in EP 680967 and U.S. Patent No.
  • Domperidone analogs are described in DE 2632870 and U.S. Patent No. 4,066,772. Vigabatrin analogs are described in U.S. Patent No. 3,960,927. Argatroban analogs are described in U.S. Patent No. 4,258,192. Mofebutazone analogs are described in GB 839057. MS-275 analogs are described in Japanese Patent Publication Hei No. 10-152462 and U.S. Patent No. 7,056,883. Sangivamycin analogs are described in U.S. Patent No. 3,423,398. Forskolin analogs are described in DE 2557784 and in U.S. Patent Nos. 4,088,659 and 4,476,140.
  • Padimate analogs are described in GB 1162337, FR 1566396, and U.S. Patent No. 3,403,207.
  • N-methyl-paroxetine analogs are described in U.S. Patent No. 4,007, 196 and WO 2007/034270.
  • Chenodeoxycholic acid analogs are described in U.S. Patent No. 4,425,273.
  • Sodium phenylbutyrate analogs are described in U.S. Patent Nos. 4,457,942 and 5,605,930.
  • 2- Methoxyestradiol analogs are described in WO 01/014405 and U.S. Patent No. 7,371,741.
  • AL-438 analogs are described in U.S. Patent Application Publication Nos.
  • APWAGl analogs are described in U.S. Patent Application Publication No. 2006/0252045.
  • HU-210 analogs are described in U.S. Patent Nos. 5,284,867, 6,096,740, and 7,297,796.
  • Icilin analogs are described in U.S. Patent No. 3,821,221.
  • 6-Iodonordihydro-capsaicin analogs are described in U.S. Patent Nos. 4,313,958, 4,401,663, 4,424,206, 4,443,473, 4,498,848, and 4,599,342.
  • TN- 16 analogs are described in U.S. Patent No. 6,693,125.
  • Farnesyl transferase inhibitors and their analogs are described in U.S. Patent Nos.
  • JNK inhibitors and their analogs are described in U.S. Patent Nos. 6,642,227, 7,084,159, 7,199,124, 7,211,594, 7,402,595, and 7,417,058.
  • RG-14620 analogs are described in U.S. Patent Nos. 6,225,346, 6,524,832, and 6,552,066.
  • Clove oil analogs are described in U.S. Patent No. 4,217,371.
  • GTP-14564 analogs are described in PCT Publication No. WO 06/135639 and in U.S. Patent Application Publication Nos.
  • Cetylpyridinium chloride analogs are described in U.S. Patent No. 4,154,744. Amsacrine analogs are described in U.S. Patent Nos. 5,604,237 and 6,207,673. Ro 48-8071 analogs are described in U.S. Patent No. 6,964,974. U 18666A analogs are described in U.S. Patent No. 5,998,433. Suxamethonium iodide analogs are described in U.S. Patent No. 5,418,226. Carboxymethylcellulose analogs are described in U.S. Patent Nos. 3,959,080, 4,988,806, and 5,023,246. Doripenem analogs are described in PCT Publication No.
  • N-(n- nonyl) deoxynojirimycin analogs are described in EP 0012278 and in U.S. Patent Nos. 4,611,058 and 4,806,650.
  • Aurintricarboxylic acid analogs are described in U.S. Patent Nos. 4,007,270, 4,1 13,879, and 4,880,788.
  • L-741,626 analogs are described in U.S. Patent Nos. 4,454,150 and 5,302,599.
  • TO- 901317 analogs are described in U.S. Patent Nos. 6,316,503 6,924,311, and 7,365,085.
  • tr ⁇ ns-4-Iodo,4'-boranyl-chalcone analogs are described in U.S. Patent Application Publication No. 2005/0176988.
  • Zinc protoporphyrin analogs are described in U.S. Patent Nos. 4,831,024 and 5,081,115. All of these references are hereby incorporated by reference.
  • the patient may also receive additional therapeutic regimens.
  • therapeutic agents may be administered with the agent or agents described herein at concentrations known to be effective for such therapeutic agents.
  • Particularly useful agents include those that treat or ameliorate symptoms of a disorder associated with a defect in the CFTR gene or protein.
  • Such agents include, for example, those that thin mucosal obstructions, treat bacterial infections, reduce inflammation, and open airway passages.
  • Exemplary agents are known therapeutics, ion-channel modulators, antiinflammatory agents, antimicrobial agents, analgesics, anesthetics, or bronchodilators.
  • Suitable agents include, e.g., 4-[4-oxo-2-thioxo- 3-(3-trifluoromethyl-phenyl)-thiazolidin-5-ylidenemethyl]-benzoic acid; (naphthalen-2-ylamino)-acetic acid (3,5-dibromo-2,4,-dihydroxy-benzylidene)- hydrazide; diarylsulfonylurea; 4-methyl-2-(5-phenyl-lH-pyrazol-3-yl)-phenol; 2-[(2-lH-indol-3-yl-acetyl)-methyl-amino]-N-(4-isopropyl-phenyl)-2-phenyl- acetamide; 6-(ethyl-phenyl-sulfonyl)-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid 2-
  • Suitable ion-channel modulators include, e.g., amiloride; 2-APB; BAY K8644; calciseptine; cilnidipine; diltiazem; flunarizine; FPL-64176; gabapentin; kuratoxin; SDZ- 202; tetrandrine; fipronil; IAA-94; 5-nitro-(3-phenylpropylamino) benzoic acid; batrachotoxin; bupivacaine; kavain; monensin; palytoxin; PD-85639; QX- 314; riluzole; and veratridine.
  • Suitable anti-inflammatory agents include, e.g., non-steroidal anti-inflammatory drugs (e.g., ibuprofen or tacrolimus), cyclooxygenase-2-specific inhibitors (e.g., rofecoxib (Vioxx®) and celecoxib (Celebrex®)), topical glucocorticoid agents, and specific cytokines directed at T lymphocyte function.
  • additional suitable anti-inflammatory agents include flubiprofen, diclofenac, and ketarolac. Antiinflammatory concentrations known to be effective may be used.
  • ibuprofen may be present in the composition at concentrations sufficient to deliver between 25-800 mg per day to the patient.
  • exemplary anti- inflammatory agents are listed in, e.g., U.S. Patent Nos. 7,112,578 and 7,199,1 19, hereby incorporated by reference.
  • Antimicrobial agents include, e.g., antibacterial, anti-fungal, and antiviral agents.
  • antibacterial agents examples include penicillins (e.g., penicillin G, ampicillin, methicillin, oxacillin, and amoxicillin), cephalosporins (e.g., cefadroxil, ceforanid, cefotaxime, and ceftriaxone), tetracyclines (e.g., doxycycline, minocycline, and tetracycline), aminoglycosides (e.g., amikacin, gentamycin, kanamycin, neomycin, streptomycin, and tobramycin), macrolides (e.g., azithromycin, clarithromycin, and erythromycin), fluoroquinolones (e.g., ciprofloxacin, lomefloxacin, moxifloxacin, and norfloxacin), and other antibiotics including chloramphenicol, clindamycin, cycloserine, isoniazid, rif
  • Anti-viral agents are substances capable of destroying or suppressing the replication of viruses.
  • antiviral agents are 1- ⁇ -D-ribofuranosyl- 1 ,2,4-triazole-3 carboxamide (ribavirin), 9-2-hydroxy-ethoxy methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, adenine arabinoside, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir.
  • Exemplary anti-viral agents are described in, e.g., U.S. Patent Nos. 6,093,550 and 6,894,033.
  • Anti-fungal agents include both fungicidal and fungistatic agents, e.g., amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, and ketoconazole.
  • fungicidal and fungistatic agents e.g., amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, and ketoconazole.
  • Exemplary anti-fungal agents are described in, e.g., U.S. Patent Nos. 5,627,153 and 7,125,842, hereby incorporated by reference.
  • any of the commonly used topical analgesics and anesthetics can be used as therapeutic agents in the invention.
  • useful anesthetics are procaine, lidocaine, tetracaine, dibucaine, benzocaine, p-buthylaminobenzoic acid 2-(diethylamino) ethyl ester HCl, mepivacaine, piperocaine, and dyclonine.
  • Exemplary anesthetics are listed in, e.g., U.S. Patent Nos. 6,562,363 and 6,569,839, hereby incorporated by reference.
  • Analgesics include opioids such as, e.g., morphine, codeine, hydrocodone, and oxycodone. Any of these analgesics may also be co- formulated with other compounds having analgesic or anti-inflammatory properties, such as acetaminophen, aspirin, codeine, naproxen, and ibuprofen. Exemplary analgesics are listed in, e.g., U.S. Patent Nos. 6,869,974 and 7,202,259, hereby incorporated by reference. Bronchodilators
  • bronchodilator can be used as a therapeutic agent in the invention described herein.
  • useful bronchodilators include, e.g., pirbuterol, epinephrine, albuterol, salbutamol, salmeterol, or levalbuterol.
  • Exemplary bronchodilators are described in, e.g., U.S. Patent Nos. 4,489,078, 4,591,588, 4,734,413, 6,299,863, and 6,555,583, hereby incorporated by reference.
  • therapeutic agents may be delivered separately or may be admixed into a single formulation.
  • routes of administration may be employed. Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (e.g., intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration).
  • systemic administration refers to all non- dermal routes of administration, and specifically excludes topical and transdermal routes of administration.
  • the agent of the invention and additional therapeutic agents are administered within at least 1, 2, 4, 6, 10, 12, 18, 24 hours, 3 days, 7 days, 14 days, or 28 days apart.
  • the dosage and frequency of administration of each component of the combination can be controlled independently.
  • one compound may be administered three times per day, while the second compound may be administered once per day.
  • Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects.
  • the compounds may also be formulated together such that one administration delivers both compounds.
  • any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein.
  • the therapeutic agents of the invention may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions of the present invention to a mammal.
  • Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
  • the additional therapeutic regimen may involve, e.g., gene therapy, lung transplantation, or a modification to the lifestyle of the patient being treated.
  • lifestyle changes may be helpful to control the disorder and include weight loss, physical exercise, diet control, reduction in alcohol intake, or reduction in smoking.
  • the drugs used in any of the combinations described herein may be covalently attached to one another to form a conjugate of formula XXX.
  • (A) is a compound listed in, e.g., Table 1, Table 2, or
  • Table 3 covalently tethered via a linker (L) to (B), a compound of, e.g., Table 1, Table 2, or Table 3.
  • Conjugates of the invention can be administered to a subject by any route and for the treatment of any disease described herein.
  • the conjugates of the invention can be prodrugs, releasing drug (A) and drug (B) upon, for example, cleavage of the conjugate by intracellular and extracellular enzymes (e.g., amidases, esterases, and phosphatases).
  • the conjugates of the invention can also be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes. The degradation of the conjugate in vivo can be controlled by the design of linker (L) and the covalent bonds formed with drug (A) and drug (B) during the synthesis of the conjugate.
  • Conjugates can be prepared using techniques familiar to those skilled in the art.
  • the conjugates can be prepared using the methods disclosed in G. Hermanson, Bioconjugate Techniques, Academic Press, Inc., 1996.
  • the synthesis of conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of drug (A), the linker, and/or drug (B).
  • commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m- nitrophenyl.
  • amides such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert- butylsulfonyl amides.
  • protecting groups for carboxyls include esters, such as methyl, ethyl, 9-fluorenylmethyl, 2- (trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho- esters, and halo-esters.
  • Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P- nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy- trityls), and silyl ethers.
  • Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls.
  • sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides).
  • Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule.
  • the conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis (2 nd Ed.), John Wiley & Sons, 1991 and P.J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.
  • the linker component of the invention is, at its simplest, a bond between drug (A) and drug (B), but typically provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking drug (A) to drug (B).
  • linking of drug (A) to drug (B) is achieved by covalent means, involving bond formation with one or more functional groups located on drug (A) and drug (B).
  • functional groups which may be employed for this purpose include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups.
  • the covalent linking of drug (A) and drug (B) may be effected using a linker, which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • a linker which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B).
  • an amine group of drug (A) may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an
  • N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions.
  • Reagents such as 2- iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulphide bridges.
  • Examples of reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents.
  • aryl halides such as reactive nitrohaloaromatic compounds
  • alkyl halides as described, for example, by McKenzie et al., J
  • Representative amino-reactive acylating agents include:
  • active esters such as nitrophenylesters or N-hydroxysuccinimidyl esters
  • acylazides e.g. wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal Biochem. 58:347 (1974); and
  • reactive moieties capable of reaction with carboxy 1 groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv Protein Chem. 3: 169 (1947).
  • Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed.
  • functional groups in drug (A) and/or drug (B) may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity.
  • methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as ⁇ -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2- bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols
  • So-called zero-length linkers involving direct covalent joining of a reactive chemical group of drug (A) with a reactive chemical group of drug (B) without introducing additional linking material may, if desired, be used in accordance with the invention.
  • the linker will include two or more reactive moieties, as described above, connected by a spacer element.
  • the presence of such a spacer permits bifunctional linkers to react with specific functional groups within drug (A) and drug (B), resulting in a covalent linkage between the two.
  • the reactive moieties in a linker may be the same (homobi functional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between drug (A) and drug (B).
  • Spacer elements in the linker typically consist of linear or branched chains and may include a C ⁇ 10 alkyl, C 2 _i 0 alkenyl, C 2 -io alkynyl, C 2 - ⁇ heterocyclyl, C 6 - I2 aryl, C 7 _ 14 alkaryl, C 3 _io alkheterocyclyl, or C 1 _ 1 o heteroalkyl.
  • the linker is described by formula (XXXI):
  • G is a bond between drug (A) and the linker; G is a bond between the linker and drug (B); Z 1 , Z 2 , Z 3 , and Z 4 each, independently, is selected from O, S, and NR 31 ; R 3 ] is hydrogen, C]_ 4 alkyl, C 2 _ 4 alkenyl, C 2 ⁇ alkynyl, C 2 _ 6 heterocyclyl, C ⁇ -n aryl, C 7 _i 4 alkaryl, C 3 _io alkheterocyclyl, or Ci_ 7 heteroalkyl; Y 1 and Y 2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; o, p, s, t, u, and v are each, independently, 0 or 1 ; and R 30 is a Ci_ 10 alkyl, C 2 _io alkenyl, C 2 _ 10 alkyny
  • homobifunctional linkers useful in the preparation of conjugates of the invention include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1 ,4-butanediol, 1 ,6- hexanediol, cyclohexanediol, and polycaprolactone diol.
  • any of the agents employed according to the present invention may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is, e.g., suitable for the oral, parenteral (e.g., intravenous or intramuscular), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route.
  • the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels (e.g., hydrogels), pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.
  • the compounds of the invention may be delivered in the form of, e.g., a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges made, for example, from gelatin
  • an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • each agent may be formulated in a variety of ways that are known in the art. Desirably, the agents are formulated together for the simultaneous or near simultaneous administration of the agents.
  • Such co-formulated compositions can include the two agents formulated together in the same, e.g., pill, capsule, or liquid. It is to be understood that, when referring to the formulation of such combinations, the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations of the invention. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be suitably matched.
  • kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, or two topical creams.
  • the kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized intravenous delivery systems, or inhalers.
  • the unit dose kit can contain instructions for preparation and administration of the compositions.
  • the kit may be, e.g., manufactured as a single use unit dose for one patient, multiple uses for a particular patient (e.g., at a constant dose or in which the individual compounds may vary in potency as therapy progresses), or the kit may contain multiple doses suitable for administration to multiple patients (e.g., bulk packaging).
  • the kit components may be assembled in, e.g., cartons, blister packs, bottles, or tubes.
  • the dosage of any of the agents of the invention will depend on the nature of the agent, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day.
  • Administration of each drug, alone or in combination, can be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be required in many cases.
  • Appropriate dosages of compounds used in the methods described herein depend on several factors, including the administration method, the severity of the disorder, and the age, weight, and health of the patient to be treated. Additionally, pharmacogenomic information (e.g., the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic) about a particular patient may affect the dosage used.
  • pharmacogenomic information e.g., the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic
  • the compounds of the invention may be employed in mechanistic assays to determine whether other single agents or combinations of agents are effective in the treatment or amelioration of a disorder associated with a defect in CFTR gene or protein using assays generally known in the art, examples of which are described herein.
  • candidate compounds may be tested, alone or in combination and contacted with cells that express a mutated CFTR (e.g., CTFR- ⁇ F508) and a fluorescent marker (e.g., yellow fluorescent protein (YFP)) to determine the functionality (e.g., openness) and/or abundance of the CFTR channels. After a suitable time, iodide is applied to the cells.
  • a mutated CFTR e.g., CTFR- ⁇ F508
  • a fluorescent marker e.g., yellow fluorescent protein (YFP)
  • the CFTR therapeutic agents of the invention accelerate YFP quenching.
  • an increase in the rate of fluorescence decay in this particular assay would indicate that the candidate compound would be a suitable CFTR therapeutic agent for the treatment of a disorder associated with a defect in CFTR gene or protein.
  • Example 1 CFTR YFP Ranking Screen and Identification of Therapeutic Agents for the Treatment of a Disorder Associated with a Defect in the CFTR Gene or Protein
  • CFTR yellow fluorescent protein (YFP) ranking screen was to select single agents from a chemical library that increase recruitment of ⁇ F508 CFTR proteins to the plasma membrane of a cell or enhance existing CFTR channel activities. This screen was performed in Fischer rat thyroid (FRT) cell lines expressing both ⁇ F508 CFTR and YFP in a 384-well plate format. Four different assay protocols were used to identify these agents.
  • FRT Fischer rat thyroid
  • the cells were incubated with candidate compounds at 37°C for 24 hours. After washing, the cells were stimulated with forskolin and a compound known to open CFTR channels before being read on a plate reader.
  • the number of ⁇ F508 CFTR channels in the plasma membrane was increased by incubating the cells at 27°C for 24 hours. The cells were then washed and treated with forskolin and the candidate compounds.
  • the cells were incubated with candidate compounds at either 27°C or at 37°C for 24 hours, the plate-washing step was omitted, and the cells were stimulated with forskolin prior to reading on a plate reader.
  • YFP fluorescence intensity was read with a plate reader at high speed before and after iodide was injected into each well of the plate. Iodide enters the cell via open CFTR channels in the plasma membrane and quenches YFP fluorescence. The rate of fluorescence decay is directly related to the total CFTR activity in the cell membranes. By increasing the total number of ⁇ F508 CFTR channels in the plasma membrane or their open probability, CFTR- ⁇ F508 therapeutic agents accelerate YFP quenching.
  • ⁇ F508 CFTR and H148Q/I152L eYFP or H148Q/I152L eYFP only were cultured in T- 175 flasks (Corning, Catalog No. 431080) or CeIlF arm high-density flasks (Fisher, Catalog No. 13-700-407) with Coon's medium (Sigma, Catalog No. F6636) containing 10% FBS (Gibco, Catalog No. 26140), 1% Penicillin-Streptomycin (Cellgro, Catalog No. 30-002-CI), 2.68 g/L sodium bicarbonate, 2 mM L-glutamine (Gibco, Catalog No.
  • T- 175 flask of cells provided enough cells to seed two 384-well plates at 50,000 cells/well and 50 ⁇ l per well; one CellFarm flask seeded about ten times as much. Once the cells were confluent in the flasks, the cells were rinsed with
  • PBS (10 ml for a T- 175 flask; 50 ml for a CellFarm flask). Trypsin-EDTA was added to the cells (5 ml for a T- 175 flask; 50 ml for a CellFarm flask). The cells were incubated at 37°C for 10-15 minutes. Cell culture media was added to neutralize the trypsin and cells were vigorously pipetted to break apart cell clumps. For passaging, the cells were split at a ratio of 1 :3 or 1 :4 (30 ml media per T- 175 flask; 500 ml media per CellFarm flask). For seeding cells on assay plates, all cell suspensions were mixed together and the cell density was counted.
  • PBS-iodide solution was made with the following concentrations of salts: 0.7 mM CaCl 2 , 2.7 mM KCl, 1.5 mM KH 2 PO 4 , 1.1 mM MgCl 2 , 154 mM NaI, and 8.1 mM NaHPO 4 , with the pH adjusted to 7.4.
  • 50,000 cells in 50 ⁇ l media were plated in each well of a 384-well plate (Matrix).
  • the drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells.
  • the plates were then incubated for 24 hours at 37°C and 5% CO 2 .
  • the plates were washed twice with DPBS and stimulated with 20 ⁇ M forskolin and 3 ⁇ M CF-P3 in DPBS for 60 minutes at room temperature before making a fluorescence reading on a plate reader (Hamamatsu FDSS-6000).
  • the plates were incubated for 24 hours at 27°C and
  • the plates were washed twice with DPBS and treated with drugs, diluted 1 : 100 in culture media and then added at a ratio of 1 :10 to the wells, and 20 ⁇ M forskolin for 60 minutes at room temperature before reading on the plate reader.
  • the plates were incubated for 60 minutes at 27°C and
  • the drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells. The plates were then incubated for 24 hours at 27°C and 5% CO 2 . The following day, the plates were stimulated with 20 ⁇ M of forskolin added to the culture media and incubated for 60 minutes at room temperature before reading on the plate reader.
  • the plates were incubated for 60 minutes at 37°C and 5% CO 2 .
  • the drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells.
  • the plates were then incubated for 24 hours at 37°C and 5% CO 2 .
  • the following day, the plates were stimulated with 20 of ⁇ M forskolin for 60 minutes at room temperature before reading on the plate reader.
  • the cells were excited with UV light at 500 nm and the fluorescence emitted at 540 nm was read at 5 Hz. After a 6-second baseline read, PBS-iodide was added to the wells.
  • the user input included t 0 (injection time), t N (fluorescence level (FL) sample time), and tg (end of data fitting point).
  • the return values included QR (fluorescence quenching rate, inverse of decay time constant tau) and FL (fluorescence level given in percentage number at t t N ).
  • FLbackground mean of FL of background wells (FLB)
  • the fluorescence level (FL) was normalized (0 to 100) at the sampling point (tu). Each FL value was taken from the kinetic fitting results to reduce noise and spikes from raw data.
  • the quenching rate (QR) was determined by exponential fitting of the fluorescence decay from the point of iodide injection (to) to the end of fitting range (t E ). QR has a dimension of s "1 .
  • QRbackground mean of QR of background wells (QRB)
  • QR u m reated was the mean value of QR from an untreated well.
  • Table 4 shows enhancement of existing CFTR channel activities in cells contacted with the candidate compound compared to untreated cells (denoted as Max Fold).
  • Table 5 shows compounds that increased recruitment of ⁇ F508 CFTR proteins to the plasma membrane in cells when contacted with the candidate compound compared to untreated cells (denoted as Max Fold).
  • Table 6 shows the reference name and chemical name for each CF reference compound.
  • Tables 7-21 show combinations of compounds that enhanced CFTR channel activities in cells contacted with the candidate compounds compared to untreated cells (denoted as Max Combination Effect (MCE, based on Max Fold) and Synergy Score (SS)).
  • MCE Max Combination Effect
  • SS Synergy Score
  • the magnitude of the synergy score indicates the strength of the synergistic interaction.
  • HDAC Inhibitors x Ion Channel Modulators Table 13. HDAC Inhibitors x Kinase Inhibitors

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention features compositions, methods, and kits for treating, or ameliorating disorders associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein (e.g., cystic fibrosis).

Description

METHODS AND COMPOSITIONS FOR THE TREATMENT OF DISORDERS ASSOCIATED WITH DEFECTS OF THE CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR
GENE OR PROTEIN
Background of the Invention
Cystic fibrosis (CF) is a lethal, autosomal-recessive genetic disease, affecting approximately 30,000 individuals in the United States. CF is characterized by defective chloride transport, resulting from a mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene encodes a linear chloride channel protein in the plasma membrane of certain epithelial cells, where it regulates the flow of chloride ions in response to phosphorylation by a cyclic AMP-dependent kinase. Many mutations of the CFTR protein have been reported, the most common of which is a deletion of a phenylalanine residue (ΔF508 CFTR). Although most people without CF have two working copies of the CFTR gene, only one is needed to prevent CF.
The principal clinical manifestation of CF is the resulting respiratory disease, characterized by airway obstruction due to the presence of thick mucus that is difficult to clear from airway passages. This airway mucus contributes to recurrent bacterial infections and impaired respiration, eventually resulting in death. Treatment of CF involves the thinning of mucosal obstructions, treating bacterial infections, using anti-inflammatory compositions to treat lung inflammation, and opening airways with bronchodilators. However, even with such treatments, frequent hospitalization is often required as the disease progresses. Accordingly, improvements are needed for the treatment of CF and other disorders associated with defects of the CFTR gene or protein. Summary of the Invention
The present invention features compositions, methods, and kits for treating or ameliorating disorders associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein (e.g., cystic fibrosis).
The invention features a composition that includes an agent selected from Table 1. Desirably, the agent is present in an amount that, when administered to a patient, is sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes a first agent selected from Table 1 or 2 and a second, different agent selected from Table 1, 2, or 3. Desirably, the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein. In another aspect, the invention features a composition that includes active ingredients and excipients, wherein the active ingredients are, for example, a first compound from Table 1 or 2 and a second compound from Table 1, 2, or 3.
In another aspect, the invention features a composition that includes a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3. Desirably, the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the CFTR gene or protein.
The compositions of the invention may be formulated, for example, for oral administration, systemic administration, or for inhalation.
The invention also features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein by administering to a patient an agent selected from Table 1 in an amount sufficient to treat or ameliorate the disorder. In another aspect, the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1 and a second, different agent selected from Table 1, 2, or 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder. In another aspect, the invention features a method for treating or ameliorating a disorder associated with a defect in the CFTR gene or protein that includes administering to a patient a first agent selected from Table 1, a second agent selected from Table 2, and a third agent selected from Table 3, wherein the agents are present in amounts that, when administered together to a patient, are sufficient to treat or ameliorate the disorder.
The agents of the methods may be administered substantially simultaneously in amounts that together are sufficient to treat or ameliorate the disorder. Alternatively, the agents may be administered within 1, 2, 4, 6, 12, or 24 hours of each other, within 7 days of each other, within 14 days of each other, or within 28 days of each other.
The agents may be administered by any appropriate route, e.g., by oral administration, systemic administration, or inhalation.
The invention also features a kit that includes at least one agent selected from Table 1 and instructions for administering the agent to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
In another aspect, the invention features a kit that includes a first agent selected from Table 1, a second, different agent selected from Table 1, 2, or 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis).
In another aspect, the invention features a kit that includes a first agent selected from Table 1, a second agent selected from Table 2, a third agent selected from Table 3, and instructions for administering the agents to a patient having a disorder associated with a defect in the CFTR gene or protein (e.g., cystic fibrosis). Combinations of the compounds described herein may be used as therapeutic agents in the compositions, methods, and kits of the present invention. Such combinations include, e.g., Corr-4a and HC toxin; Corr-4a and valproic acid; Corr-4a and suberoylanilide hydroxamic acid; atorvastatin calcium and HC toxin; prednisolone and suberoylanilide hydroxamic acid; quinestrol and suberoylanilide hydroxamic acid; chlormadinone acetate and Corr-4a; 2-APB and histone deacetylase inhibitor III; staurosporine and suberoylanilide hydroxamic acid; BAY 60-7550 and suberoylanilide hydroxamic acid; drotaverine hydrochloride and suberoylanilide hydroxamic acid; BAY 60-7550 and CF-C3; CF-C6 and gliquidone; Corr-4a and LY
294002; Corr-4a and flunixin meglumine; clofarabine and quinestrol; and CF- P5 and suberoylanilide hydroxamic acid.
By "an amount sufficient" is meant the amount of a compound, alone or in combination with another compound or therapeutic regimen, required to treat or ameliorate a disorder, such as cystic fibrosis, in a clinically relevant manner. A sufficient amount of an active compound used to practice the present invention for therapeutic treatment of, e.g., cystic fibrosis, varies depending upon the manner of administration, age, and general health of the patient. Ultimately, the prescribers will decide the appropriate amount and dosage regimen. Additionally, an effective amount may be an amount of compound in the combination of the invention that is safe and efficacious in the treatment of a patient having a disorder, such as cystic fibrosis, over each agent alone as determined and approved by a regulatory authority (such as the U.S. Food and Drug Administration). By "candidate compound" is meant a chemical, e.g., naturally-occurring or artificially-derived. Candidate compounds may include, for example, peptides, polypeptides, synthetic organic molecules, naturally-occurring organic molecules, nucleic acid molecules, peptide nucleic acid molecules, and components and derivatives thereof. Compounds useful in the invention include those described herein in any of their pharmaceutically acceptable forms, including isomers such as diastereomers and enantiomers, salts, solvates, and polymorphs thereof, as well as racemic mixtures. Compounds useful in the invention may also be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, (e.g., 2H, 3H, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36Cl). Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically- labeled reagent in place of a non-isotopically-labeled reagent.
By "disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein" is meant any disorder resulting from a mutation of the CFTR gene or protein (e.g., a deletion of F508, a G542X mutation, a G551D mutation, a N1303K mutation, or a W1282X mutation). Exemplary disorders include cystic fibrosis, the congenital absence of the vas deferens, and some forms of pancreatitis.
By a "high dosage" is meant at least 5% more (e.g., at least 10%, 20%, 30%, 40%, 50%, 100%, 150%, 200%, or 300%) than the highest standard recommended dosage of a particular compound formulated for a given route of administration for treatment of any disease or condition. For example, a high dosage of an agent that treats or prevents cystic fibrosis and that is formulated for intravenous administration may differ from a high dosage of the same agent formulated for oral administration.
By a "low dosage" is meant at least 5% less (e.g., at least 10%, 20%, 50%, 80%, 90%, or 95%) than the lowest standard recommended dosage of a particular compound formulated for a given route of administration for the treatment of any disease or condition. By "patient" is meant any animal, e.g., a mammal (e.g., a human).
Other animals that can be treated using the compositions, methods, and kits of the invention include, e.g., horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish, and birds. A patient who is being treated for a disorder associated with a CFTR defect (e.g., cystic fibrosis) is one who has been diagnosed by a medical practitioner as having such a condition. Diagnosis may be performed by any suitable means, such as those described herein. One in the art will understand that patients of the invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors, such as age, genetics, or family history. By "pharmaceutically acceptable salt" is meant salts 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, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Representative acid addition salts include, e.g., acetate, ascorbate, aspartate, benzoate, citrate, digluconate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, lactate, malate, maleate, malonate, mesylate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, and ethylamine.
By "sustained release" or "controlled release" is meant that the therapeutically active component is released from the formulation at a controlled rate such that therapeutically beneficial blood levels (but below toxic levels) of the component are maintained over an extended period of time ranging from, e.g., about 12 to about 24 hours, thus, providing, for example, a 12-hour or a 24-hour dosage form.
By "systemic administration" is meant any non-dermal route of administration, and specifically excludes topical and transdermal routes of administration. By "therapeutic agent" is meant any agent that produces a healing, curative, stabilizing, or ameliorative effect.
By "treating or ameliorating" is meant ameliorating a condition or symptoms of the condition (e.g., cystic fibrosis) before or after its onset. As compared with an equivalent untreated control, such amelioration or degree of treatment is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% as measured by any standard technique.
Exemplary therapeutic agents used for the treatment of any patient that has been diagnosed with a disorder associated with defects of a CFTR gene or protein are listed in Tables 1, 2, and 3.
Table 1
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Table 2
Figure imgf000021_0002
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Table 3
(+)-c«-Diltiazem (e.g., hydrochloride salt)
(±)-Methadone (e.g., hydrochloride salt)
1-Octanol
Chlorotoxin from Leiurus quinquestriatus
Cinnarizine
Fluspirilene
FPL 64176
FS-2
Gabapentin
HA- 1077
Ivermectin
Kurtoxin
Mibefradil (e.g., dihydrochloride hydrate salt)
Neomycin (e.g., trisulfate salt hydrate)
NNC 55-0396
N-SaI icyloyltryptamine
Penfluridol
Phloretin
Protopine (e.g., hydrochloride salt)
SNX-482 synthetic
S-Petasin tert-Butyl bicyclo[2.2.2]phosphorothionate
Thioridazine (e.g., hydrochloride salt)
Veratridine
Other features and advantages of the invention will be apparent from the detailed description and from the claims.
Brief Description of the Drawings
Figure 1 is a representative graph showing the fluorescence of FRT cells (ΔF508; eYFP) incubated with DMSO alone (FLDMSo)> with forskolin alone (FLFSKX or with forskolin and a candidate compound (FLFSK+GEN) before and after contact with an iodide solution. Detailed Description of the Invention
We have discovered compounds that, alone or in combination, increase the recruitment of ΔF508 cystic fibrosis transmembrane conductance regulator (CFTR) proteins to the plasma membrane of a cell or enhance the activity of ΔF508 CFTR proteins already present in the plasma membrane. Thus, these compounds may be useful for treating a patient that has been diagnosed with a disorder associated with a defect in the CFTR gene or protein. Optionally, analogs of these compounds may be employed. In the case of cystic fibrosis, for example, such administration may decrease mucus production, decrease sputum viscosity, decrease blood pressure of the lung, reduce inflammation of the sinuses, lung, and pancreas, decrease thickened secretions that block bile ducts, control CF-related diabetes, or maximize organ function.
Diagnosis of Disorders Associated with Defects of the CFTR Gene or Protein
The compositions, methods, and kits of the present invention are useful for treating any patient that has been diagnosed with a disorder associated with defects of the CFTR gene or protein (e.g., cystic fibrosis). One in the art will understand that patients of the invention may have been subjected to standard tests or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors.
Diagnosis of these disorders may be performed using any standard method known in the art, such as those described herein. Methods for diagnosing CFTR-defect disorders are described, for example, in U.S. Patent Nos. 3,902,847, 4,273,869, 4,469,788, and 7,160,729, hereby incorporated by reference. CFTR-defect disorders, e.g., CF, may be diagnosed and monitored using, for example, sweat (or chloride) tests to measure the amount of chloride in the sweat, which involves stimulating sweat from the patient with a mild electric current. The sweat is collected onto a gauze pad and analyzed. Higher than normal concentrations of chloride may be suggestive of a CFTR-defect disorder. Blood tests may also be performed to test for mutations in the CFTR gene. Chest x-rays, pulmonary function tests (e.g., diagnostic tests that help to measure the lungs' ability to exchange oxygen and carbon dioxide), sputum cultures, stool evaluations (e.g., to measure stool fat absorption), and pancreatic function tests may also be used to diagnosis CFTR-defect disorders. The use of any of the above tests or any other tests known in the art may be used to monitor the efficacy of the present treatment.
Therapeutic Agents
Exemplary therapeutic agents used for the treatment of any patient that has been diagnosed with a disorder associated with defects of a CFTR gene or protein are listed in Tables 1, 2, and 3. Preferred agents include, e.g., statins, steroids, flavonoids, dihydropyridines, HDAC inhibitors, sulfonylureas, PPAR agonists, estrogen/estradiol receptor modulators, PDE inhibitors and adenosine receptor modulators, kinase inhibitors, NSAIDs and leukotriene antagonists, proton pump inhibitors, channel modulators, and receptor modulators.
Statins and Analogs or Derivatives Thereof
Statins may be used as therapeutic agents in the compositions, methods, and kits of the invention, alone or in combination with additional agents. Statins of the invention include atorvastatin; cerivastatin; fluvastatin; lovastatin; rosuvastatin; acitemate; amlodipine/atorvastatin; BAY102987; BAY
X 2678; BB476; bervastatin; BMY21950; BMY22089; colestolone; CP83101 ; dalvastatin; DMP565; ezetimibe/simvastatin; glenvastatin; L659699; L669262; mevastatin; nicotinic acid/lovastatin; nicotinic acid/simvastatin; P882222; P882284; PD 134965; PD 135022; pitavastatin; rosuvastatin; RP61969; S2468;
SC371 1 1 ; SC45355; simvastatin; SQ33600; SR12813; SR45023A; U20685; and U88156.
The synthesis of statins and statin derivatives is described, for example, in U.S. Patent Nos. 2,956,066, 3,288,826, 4,397,786, 4,803,292, 6,689,590, 7,199,102, and 7,297,808, hereby incorporated by reference. Additional statins and analogs thereof useful in the methods and compositions of the present invention are described, for example, in U.S. Patent Nos. 3,983,140, 4,231,938, 4,282,155, 4,293,496, 4,294,926, 4,319,039, 4,343,814, 4,346,227, 4,351,844, 4,361,515, 4,376,863, 4,444,784, 4,448,784, 4,448,979, 4,450,171, 4,503,072, 4,517,373, 4,661,483, 4,668,699, 4,681,893, 4,719,229, 4,738,982, 4,739,073, 4,766,145, 4,782,084, 4,804,770, 4,841,074, 4,847,306, 4,857,546, 4,857,547, 4,940,727, 4,946,864, 5,001,148, 5,006,530, 5,075,311, 5,112,857, 5,116,870, 5,120,848, 5,166,364, 5,173,487, 5,177,080, 5,273,995, 5,276,021, 5,369,123, 5,385,932, 5,502,199, 5,763,414, 5,877,208, and 6,541,511, and U.S. Patent Application Publication Nos. 2002/0013334 Al , 2002/0028826 Al, 2002/0061901 A 1 , and 2002/0094977 A 1.
Steroids and Analogs or Derivatives Thereof
Steroids may be used as therapeutic agents in the compositions, methods, and kits of the invention, alone or in combination with additional agents. Steroids include, e.g., sex hormones and corticosteroids (e.g., glucocorticoids and mineralcorticoids). Exemplary steroids of the invention include corticosterone; fluocinonide; fluprednisolone; rimexolone; triamcinolone; 11 -alpha, 17-alpha,21-trihydroxypregn-4-ene-3,20-dione; 11- beta, 16-alpha, 17,21 -tetrahydroxypregn-4-ene-3,20-dione; 1 1 -beta, 16- alpha, 17,2 l-tetrahydroxypregn-l,4-diene-3,20-dione; 1 l-beta,17-alpha,21- trihydroxy-6-alpha-methylpregn-4-ene-3,20-dione; 11-dehydrocorticosterone; 1 1-deoxycortisol; 11 -hydroxy- l,4-androstadiene-3, 17-dione; 1 1- ketotestosterone; 14-hydroxyandrost-4-ene-3,6,17-trione; 15,17- dihydroxyprogesterone; 16-methylhydrocortisone; 17,21 -dihydroxy- 16-alpha- methylpregna- 1,4,9(1 l)-triene-3,20-dione; 17-alpha-hydroxypregn-4-ene-3,20- dione; 17-alpha-hydroxypregnenolone; 17-hydroxy-16-beta-methyl-5-beta- pregn-9(l l)-ene-3,20-dione; 17-hydroxy-4,6,8(14)-pregnatriene-3,20-dione; 17-hydroxypregna-4,9(l l)-diene-3,20-dione; 18-hydroxycorticosterone; 18- hydroxycortisone; 18-oxocortisol; 21-deoxyaldosterone; 21-deoxycortisone; 2- deoxyecdysone; 2-methylcortisone; 3-dehydroecdysone; 4-pregnene-17- alpha,20-beta, 21-triol-3,l l-dione; 6,17,20-trihydroxypregn-4-ene-3-one; 6- alpha-hydroxy Cortisol; 6-alpha-fluoroprednisolone; 6-alpha- methylprednisolone; 6-alpha-methylprednisolone 21 -acetate; 6-alpha- methylprednisolone 21 -hemisuccinate sodium salt; 6-beta-hydroxy Cortisol; 6- alpha; 9-alpha-difluoroprednisolone 21 -acetate 17-butyrate; 6- hydroxycorticosterone; 6-hydroxydexamethasone; 6-hydroxyprednisolone; 9- fluorocortisone; alclometasone dipropionate; aldosterone; algestone; alphaderm; amadinone; amcinonide; anagestone; androstenedione; anecortave acetate; beclomethasone; beclomethasone dipropionate; beclomethasone dipropionate monohydrate; betamethasone 17-valerate; betamethasone sodium acetate; betamethasone sodium phosphate; betamethasone valerate; bolasterone; budesonide; calusterone; chlormadinone; chloroprednisone; chloroprednisone acetate; cholesterol; clobetasol; clobetasol propionate; clobetasone; clocortolone; clocortolone pivalate; clogestone; cloprednol;
Cortisol; Cortisol acetate; Cortisol butyrate; Cortisol cypionate; Cortisol octanoate; Cortisol sodium phosphate; Cortisol sodium succinate; Cortisol valerate; cortisone; cortisone acetate; cortodoxone; daturaolone; deflazacort,
21 -deoxycortisol, dehydroepiandrosterone; delmadinone; deoxycorticosterone; deprodone; descinolone; desmosterol; desogestrel; desonide; desoximethasone; dexafen; dexamethasone; dexamethasone 21 -acetate; dexamethasone acetate; dexamethasone sodium phosphate; dichlorisone; diflorasone; diflorasone diacetate; diflucortolone; dihydroelatericin a; domoprednate; doxibetasol; ecdysone; ecdysterone; endrysone; enoxolone; flucinolone; fludrocortisone; fludrocortisone acetate; flugestone; flumethasone; flumethasone pivalate; flumoxonide; flunisolide; fluocinolone; fluocinolone acetonide; 9- fluorocortisone; fluocortolone; fluorohydroxy androstenedione; fluorometholone; fluorometholone acetate; fluoxymesterone; fluprednidene; flurandrenolide; fluticasone; fluticasone propionate; formebolone; formestane; formocortal; gestonorone; glyderinine; halcinonide; hyrcanoside; halometasone; halopredone; haloprogesterone; hydrocortiosone cypionate; hydrocortisone; hydrocortisone 21 -butyrate; hydrocortisone aceponate; hydrocortisone acetate; hydrocortisone buteprate; hydrocortisone butyrate; hydrocortisone cypionate; hydrocortisone hemisuccinate; hydrocortisone probutate; hydrocortisone sodium phosphate; hydrocortisone sodium succinate; hydrocortisone valerate; hydroxyprogesterone; inokosterone; isoflupredone; isoflupredone acetate; isoprednidene; meclorisone; mecortolon; medrogestone; medroxyprogesterone; medrysone; megestrol; megestrol acetate; melengestrol; meprednisone; methandrostenolone; methylprednisolone; methylprednisolone aceponate; methylprednisolone acetate; methylprednisolone hemisuccinate; methylprednisolone sodium succinate; methyltestosterone; metribolone; mometasone; mometasone furoate; mometasone furoate monohydrate; nisone; nomegestrol; norgestomet; norvinisterone; oxymesterone; paramethasone; paramethasone acetate; ponasterone; prednisolamate; prednisolone; prednisolone 21 -hemisuccinate; prednisolone acetate; prednisolone farnesylate; prednisolone hemisuccinate; prednisolone-21 (beta-D-glucuronide); prednisolone metasulphobenzoate; prednisolone sodium phosphate; prednisolone steaglate; prednisolone tebutate; prednisolone tetrahydrophthalate; prednisone; prednival; prednylidene; pregnenolone; procinonide; tralonide; progesterone; promegestone; rhapontisterone; roxibolone; rubrosterone; stizophyllin; tixocortol; topterone; triamcinolone acetonide; triamcinolone acetonide 21-palmitate; triamcinolone diacetate; triamcinolone hexacetonide; trimegestone; turkesterone; and wortmannin.
Other compounds that may be used as a substitute for or in addition to a corticosteroid in the compositions, methods, and kits of the invention include, e.g., A-348441 ; adrenal cortex extract; alsactide; amebucort; amelometasone;
ATSA; bitolterol; CBP-201 1 ; cebaracetam; CGP-13774; ciclesonide; ciclometasone; clobetasone butyrate; cloprednol; collismycin A; cucurbitacin
E; deflazacort; deprodone propionate; dexamethasone acefurate; dexamethasone linoleate; dexamethasone valerate; difluprednate; domoprednate; ebiratide; etiprednol dicloacetate; fluazacort; flumoxonide; fluocortin butyl; fluocortolone monohydrate; GR-250495X; halometasone; halopredone; HYC- 141 ; icomethasone enbutate; itrocinonide; L-6485
(Vicuron), Lipocort; locicortone; meclorisone; naflocort; NCX-1015; NCX- 1020; NCX-1022; nicocortonide; NIK-236; NS-126; Org-2766; Org-6632; P 16CM, propylmesterolone; RGH-1113; rofleponide; rofleponide palmitate; RPR-106541 ; RU-26559; Sch-19457; T25; TBI-PAB; ticabesone propionate; tifluadom; timobesone; TSC-5; and ZK-73634. Standard recommended dosages for corticosteroids are provided, e.g., in the Merck Manual of Diagnosis & Therapy (17th Ed. MH Beers et al., Merck & Co.) and Physicians' Desk Reference 2003 (57th Ed. Medical Economics Staff et al., Medical Economics Co., 2002), hereby incorporated by reference. The synthesis of steroids and steroid derivatives is described, for example, in DE 2361120 and in U.S. Patent Nos. 2,760,966, 2,760,975, 3,927,046, 4,102,925, 4,183,864, and 4,267,376, hereby incorporated by reference.
Flavonoids and Analogs or Derivatives Thereof
Flavonoids may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary flavonoids of the invention include, e.g., apigenin, genistein, isoliquiritigenin, quercetin, or 2-hydroxyflavanone. Additional flavonoids include taxifolin, catechin, epicatechin, eriodictyol, naringenin, troxerutin, chrysin, tangeretin, luteolin, epigallocatechin and epigallocatechin gallate, fisetin, kaempferol, galangin, gallocatechin, and epicatechin gallate.
The synthesis of flavonoids and flavonoid derivatives is described, for example, in U.S. Patent Nos. 4,617,293, 5,756,538, 6,004,998, 6,028,088, 6,087,385, and 7,138,429, hereby incorporated by reference.
Dihydropyridines and Analogs or Derivatives Thereof
Dihydropyridines may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary dihydropyridines of the invention are felodipine, isradipine, nimodipine, or nisoldipine. Additional dihydropyridines include, e.g., nicardipine, nifedipine nitrendipine, lacidipine, nilvadipine, manidipine, barnidipine, benidipine, azelnidipine, and lercanidipine. The synthesis of dihydropyridines and dihydropyridine derivatives is described, for example, in DE 2904552, EP 63365, EP 106275, and in U.S. Patent Nos. 4,044,141, 4,179,570, 4,220,649, 4,448,964, 5,492,923, 5,661,157, 5,712,296, 6,239, 155, and 7,074,931, hereby incorporated by reference.
Histone Deacetylase Inhibitors and Analogs or Derivatives Thereof Histone deacetylase (HDAC) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary HDAC inhibitors of the invention are suberoylanilide hydroxamic acid (SAHA) and derivatives thereof (e.g.,
CAY10398 and those described in U.S. Patent No. 6,51 1,990); derivatives of hydroxamic acid; trichostatin A; trichostatin C; trichostatin D; CG- 1521 ; sulfonamide hydroxamic acid compounds; biaryl hydroxamate; NVP-LAQ824; EX-2; the diamide or amide-carbamate hydroxamic acids SK-658, SK-692, and SK-691 ; LAQ824/LBH589 (panobinostat); pyroxamide; oxamflatin ((2E)-5-[3- [(phenylsulfonyl) amino]phenyl]-pent-2-en-4-ynohydroxamic acid); metacept- 1 ; A- 161906; scriptaid; CRA026440; PXD-101 (belinostat); CHAP (also called CHAPl); MW2796; MW2996; carboxycinnamic acid bishydroxamide (CBHA); suberohydroxamic acid SBHA; 6-(3-chlorophenylureido) caproic hydroxamic acid (3-Cl-UCHA); azelaic-l-hydroxamate-9-anilide (AAHA); APHA-I and APHA-8; the hydroxamic acid compounds disclosed in Andrews et al. {Intl. J. Parasitol. 30:761-768, 2000) and Nishino et al. {Bioorg. Med.Chem. 12:5777-5784, 2004); short-chained fatty acids and their derivatives (e.g., valproic acid and valproic acid analogs described in PCT Publication No. WO 94/006745, U.S. Patent Nos. 4,558,070, 4,699,927,
4,895,873, 5,101,070, and 5,162,573, by Formula I of U.S. Patent Publication No. 2004/0087652, sodium butyrate, tributyrin, phenylbutyrate, and AN-9 (pivaloyloxymethyl butyrate)); bicyclic aryl-N-hydroxycarboxamides; benzamides (e.g., sirtinol, MGCDO 103, M344, MS27-275 (also called MS- 275), MGCDO 103, CI994 (tacedinaline/acetylinaline), compounds disclosed in U.S. Patent No. 7,244,751, "compound 4" in Moradei et al. (J. Med. Chem. 50:5543-45546, 2007), and compounds disclosed in Andrews et al. {Bioorg. Med. Chem. Lett. 18:2525-2529, 2008) and Andrews et al. {Bioorg. Med. Chem. Lett. 18:2580-2584, 2008)); peptidic compounds including certain tripeptides, cyclic tetrapeptides, cyclic disulfides, and ketone derivatives thereof (e.g., HC toxin, chlamydocin, apicidins, trapoxin A, trapoxin B, depudecin, WF-3161, WF27082 (U.S. Patent No. 6,656,905), FR901228, FR235222 and derivatives thereof, compounds of formula I in U.S. Patent No. 5,922,837, and FK-228 (depsipeptide/romidepsin) and derivatives thereof); sirtuin inhibitors (e.g., sirtinol, splitomicin and suramin sodium); pyroxamides and derivatives thereof; microbial metabolites exhibiting HDAC inhibitory activity; MG2856; BML-210 (N-(2-aminophenyl)-N'-phenyloctanediamide; also called CAY10433); and carmbamic acid compounds (e.g., compounds disclosed in U.S. Patent No. 6,888,027, PCT Publication Nos. WO 02/026703, WO 02/026696, and WO 03/082288, and in Andrews et al. (Antimicrob. Agents Chemother. 52:1454-1461, 2008)).
Additional HDAC inhibitors are described in Saito, et al. (Proc. Natl. Acad. ScL USA 96:4592-4597, 1999), Furamai et al. {Proc. Natl. Acad. Sci. USA 98:87-92, 2001), Komatsu et al. {Cancer Res. 61 :4459-4466, 2001), Su et al. {Cancer Res. 60:3137-3142, 2000), Suzuki et al. {J. Med. Chem. 42:3001- 3003, 1999), in U.S. Patent Application Publication Nos. 2008/0146623,
2008/0207590, 2008/0096889, 2008/0161401, 2008/0214617, 2007/0135438, 2007/0135424, 2008/0221157, 2007/0135424, 2008/0227826, 2007/0129368, 2008/0139535, 2008/0027059, 2008/0132503, 2008/0132459, 2008/0039509, 2007/0142393, 2008/0108601, 2008/0096920, 2007/0293530, 2007/0281934, 2007/0225373, 2007/018507, 2007/0213330, 2007/0184979, 2007/0155730, 2007/0149495, 2005/0176686, 2008/0176849, 2008/0207694, 2008/0228005, 2008/0139547, 2008/0096920, 2008/0085896, 2008/0070976, 2008/0070934, 2008/0033015, 2008/0015216, 2008/0015190, 2008/0004290, 2007/0213392, 2007/0167499, 2007/0155785, 2007/0043043, and 2008/000431 1, in U.S. Patent Nos. 5,055,608, 5,175,191, 5,369, 108, 5,608,108, 5,700,811, 5,773,474, 5,932,616, 6,087,367, 6,511,990, 6,888,027, and 7,235,688, and in PCT Publication Nos. WO 04/009536, WO 01/18171, WO 02/246144, WO 02/22577, WO 02/30879, WO 01/38322, WO 01/70675, WO 00/71703, WO 00/21979, WO 98/40080, and WO 05/053610, hereby incorporated by reference.
Sulfonylureas and PPAR Agonists and Analogs or Derivatives Thereof
Sulfonylureas and peroxisome proliferator-activated receptor (PPAR) agonists may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary sulfonylureas and PPAR agonists are gliquidone; glitazones (e.g., balaglitazone, troglitazone, pioglitazone, ciglitazone, englitazone, rosiglitazone, darglitazone, englitazone, netoglitazone, KRP-297, JTT-501, NC-2100, NIP-223, MCC-555, L-764486, and CS-Ol 1); acetohexamide; chlorpropamide; tolbutamide; tolazamide; glipizide; gliclazide; glibenclamide; glyclopyramide; glimepiride; GI262570; [(S)-2-(2-benzoylphenylamino)-3-[4- [2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl] propionic acid; GW347845; AA-10090; AD-5075; AMG-131 ; ARH-049020; AVE-0847, AVE-8134; AY-31637; BAY-549801; bexarotene; BM-131246; BM-501050; CLX-0921 ; CLX-0940; DRF-10945; DRF-4832; E-3030; farglitazar; fenofibrate/metformin; GW-0072; GW- 1929; GW-2570; GW-409544; GW- 409890; GW-501516; GW-5393; GW-590735; GW-7282; GW-9578; KRP- 101 ; KT-6207; L-764406; LF-200337; LG-101506; LR-90; LY-465608; LY- 510929; LY-518674; MBX- 102; MK-0767; muraglitazar; naveglitazar; NC- 2100; NS-220; ONO-5129; oxeglitazar; PD-72953; R-1 19702; ragaglitazar; reglitazar; SB-219994; tesaglitazar; 641597; clofibrate; gemfibrozil; ciprofibrate; bezafibrate; and TY-51501.
Additional sulfonylureas and PPAR agonists are described in FR 1510714, GB 912789, GB 853555, GB 860303, DE 2343606, DE 2149070, DE 2000339, DE 201 1 126, DE 2012138, DE 2951 135, EP 306228, PCT
Publication No. WO 93/21 146, and in U.S. Patent Nos. 3,174,901 , 3,262,850, 3,349,124, 3,501,495, 3,669,966, 3,708,486, 3,781,328, 3,948,973, 4,337,267, 4,379,785, 5,002,953, 5,260,275, 5,466,861, 5,859,037, and 6,812,250, hereby incorporated by reference.
Estrogen/Estradiol Receptor Modulators and Analogs or
Derivatives Thereof
Estrogen and estradiol receptor modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary estrogen and estradiol receptor modulators are quinestrol and its metabolites (e.g., ethinyl estradiol); megestrol; melengestrol; desmosterol; centchroman; estrogen; progestogen; estradiol; alfatradiol; estriol; droloxifene; raloxifene; lasofoxifene; TSE-424; tamoxifen; idoxifene; LY353381 ; LYl 17081 ; toremifene; fulvestrant; 4-[7-(2,2-dimethyl- 1 -oxopropoxy-4-methyl-2-[4-[2-( 1 -piperidiny l)ethoxy]phenyl]-2H- 1 - benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate; 4,4'- dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone; SH646; clomiphene; cycladiene; nafoxidine; nitromifene citrate; 13-ethyl-17α-ethynl-17β- hydroxygona-4-9-1 l-trien-3-one; diphenol hydrochrysene; erythro-MEA; allenolic acid; cyclofenyl; chlorotrianisene; ethamoxytriphetol; triparanol; CI- 626; CI-680; MER-25; U-11.555A; U-I l,100A; ICI-46,669; ICI-46,474; and CN-55,945.
Additional estrogen and estradiol receptor modulators are described in PCT Publication No. WO 95/10513, EP 54168, EP 62503, EP 260066, EP 95875, and in U.S. Patent Nos. 2,096,744, 2,233,025, 2,61 1 ,773, 2,835,681, 2,891,079, 3,1 17,966, 3,159,543, 3,231,567, 3,356,573, 3,400, 137, 4,418,068, 4,696,949, 4,839,155, 5,047,431, 5,393,763, 5,457,1 17, 5,478,847, 5,641,790, 6,599,921, 6,838,548, 7,138,426, 7, 151,196, and 7,429,576, hereby incorporated by reference. Phosphodiesterase Inhibitors and Analogs or Derivatives Thereof
Phosphodiesterase (PDE) inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Type I PDE inhibitors include (3-α,16-α)-eburnamenine-14-carboxylic acid ethyl ester (Vinpocetine); l,8-methoxymethyl-3-isobutyl-l-methylxantine (MIMX); l-carboxy-23A4Mb^6,6a,6bJ^8a,8b,9,10, 10a,14, 16, 17,17a,17b,18, 19,19a, 19b, 20,21,21a,21b,22,23,23a-dotriacontahydro-14- hydroxy-8a, 1 Oa-bis(hydroxymethyl)- 14-(3-methoxy-3-oxopropyl)- 1 ,4,4a, 6,6a,17b,19b,21b-octamethyl beta-D-glucopyranosiduronic acid (Ks-505a); cis- 5,6a,7,8,9,9a-hexahydro-2-(4-(trifluoromethyl)phenylmethyl)-5-methyl- cyclopent (4,5)imidazo(2,l-b)purin-4(3H)-one (SCH 51866); and 2-o- propoxyphenyl-8-azapurine-6-one (Zaprinast). Other Type I PDE inhibitors are described in U.S. Patent Application Publication Nos. 2004/0259792 and 2005/0075795.
Type II PDE inhibitors include erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA); 2,3,6,7-tetrahydro-9,10-dimethoxy-3-methyl-2-((2,4,6- trimethylphenyl)imino)-4H-pyrimido(6, 1 -a)isoquinolin-4-one (trequinsin); ND7001 ; and BAY 60-7550. Other Type II PDE inhibitors are described in U.S. Patent Application Publication No. 2003/0176316.
Type III PDE inhibitors include 3-isobutyl-l-methylxanthine (IBMX); 6-dihydro-2-methyl-6-oxo-3,4'-bipyridine)-5-carbonitrile (milrinone); zardaverine; and N-cyclohexyl-4-(( 1 ,2-dihydro-2-oxo-6-quinolinyl)oxy)-N- methyl-butanamide (cilostamide). Other Type III PDE inhibitors are described in EP 0653426, EP 0294647, EP 0357788, EP 0220044, EP 0326307, EP 0207500, EP 0406958, EP 0150937, EP 0075463, EP 0272914, and EP 01 12987, in U.S. Patent Nos. 4,963,561, 5,141,931, 6,897,229, and 6,156,753, in U.S. Patent Application Publication Nos. 2003/0158133, 2004/0097593, 2006/0030611, and 2006/0025463, in PCT Publication Nos. WO 96/15117, and in DE 2825048, DE 2727481 , DE 2847621 , DE 3044568, DE 2837161 , and DE 3021792. Exemplary Type IV PDE inhibitors include 4-(3-cyclopentyloxy-4- methoxyphenyl)-2-pyrrolidone (rolipram); roflumilast; 4-(3-butoxy-4- methoxybenzyl)-2-imidazolidinone (Ro20-1724); and etazolate. Other Type IV PDE inhibitors are described in U.S. Patent Nos. 3,892,777, 4,193,926, 4,655,074, 4,965,271, 5,096,906, 5,124,455, 5,272,153, 6,569,890, 6,953,853, 6,933,296, 6,919,353, 6,953,810, 6,949,573, 6,909,002, and 6,740,655, in U.S. Patent Application Publication Nos. 2003/0187052, 2003/0187257, 2003/0144300, 2003/0130254, 2003/0186974, 2003/0220352, 2003/0134876, 2004/0048903, 2004/0023945, 2004/0044036, 2004/0106641, 2004/0097593, 2004/0242643, 2004/0192701, 2004/0224971, 2004/0220183, 2004/0180900, 2004/0171798, 2004/0167199, 2004/0146561, 2004/0152754, 2004/0229918, 2005/0192336, 2005/0267196, 2005/0049258, 2006/0014782, 2006/0004003, 2006/0019932, 2005/0267196, 2005/0222207, 2005/0222207, 2006/0009481, and in PCT Publication Nos. WO 92/079778 and WO 95/01338. Exemplary Type V PDE inhibitors include sildenafil; vardenafil; and tadalafil. Other Type V PDE inhibitors are described in U.S. Patent Nos. 6,992, 192, 6,984,641, 6,960,587, 6,943, 166, 6,878,711, and 6,869,950, and in U.S. Patent Application Publication Nos. 2003/0144296, 2003/0171384, 2004/0029891, 2004/0038996, 2004/0186046, 2004/0259792, 2004/0087561, 2005/0054660, 2005/0042177, 2005/0245544, and 2006/0009481.
Exemplary Type VI PDE inhibitors include those described in U.S. Patent Application Publication Nos. 2004/0259792, 2004/0248957, 2004/0242673, and 2004/0259880.
An exemplary Type VII PDE inhibitor includes BRL-50481. Other Type VII PDE inhibitors include those described in U.S. Patent Nos.
6,838,559, 6,753,340, 6,617,357, and 6,852,720, in U.S. Patent Application Publication Nos. 2003/0186988, 2003/0162802, 2003/0191 167, 2004/0214843, and 2006/0009481, and in PCT Publication No. WO 00/68230.
Tofisopam is an exemplary Type X PDE inhibitor. Tofisopam analogs are described in HU 155572, GB 1202579, and in U.S. Patent No. 3,736,315. Kinase Inhibitors and Analogs and Derivatives Thereof
Kinase inhibitors (e.g., tyrosine, GSK3, p38, CAMKK, Akt, Cdk,
EGFR, JNK, MAP, MEK, MLCK, PB, or VEGFR kinase inhibitors) may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary kinase inhibitors are bevacizumab; BIBW 2992; cetuximab; trastuzumab; sunitinib; erlotinib; neratinib; nilotinib; lapatinib; panitumumab; vandetinib; E7080; ranibizumab; pegaptanib; sorafenib; imatinib; motesanib; leflunomide; ZDl 839; erlotinib; canertinib; squalamine; SU 4312; SU 5416; ZD4190; vatalanib; PKI-166; GW2016; EKB-509; trastuzumab; EKB-569; kahalide; F CEP-701 ; CEP-751 ;
MLN-518; PKC-412; phenoxodiol; C225; rhu-Mab; MDX-H210; 2C4; MDX-
447; ABX-EGF; IMC-ICl 1 ; tyrphostins; gefitinib; sirolimus, rapamycin; dasatinib; staurosporine; LY 294002; sangivamycin; genistein; dicoumarol; staurosporine; indirubin; OSI-7904; ZD6474; ZD6126 (ANG453); ZD1839; semaxanib (SU5416); AMG706; AGO 13736; VELCADE®; AZD2171 ; XL880;
CHIR-265; n-(4-chlorophenyl)-2-[pyridin-4-ylmethyl)amino]benzamide; trans- benzyl(chloro)-bis(triphenylphosphine) palladium (II); and purvalanol A.
Exemplary kinase inhibitors are those described in DE 2347682 and EP
564409, and in U.S. Patent Nos. 3,929,992, 4,284,786, 5,192,756, 5,521,184, 5,618,829, 6,596,746, 6,794,393, 6,927,293, 6,987,113, 7,081,454, 7,101,884,
7,109,204, 7,186,723, 7,223,757, 7,371,754, and 7,470,696, hereby incorporated by reference.
Non-Steroidal Anti-Inflammatory Drugs and Leukotriene Antagonists and Analogs or Derivatives Thereof
Non-steroidal anti-inflammatory drugs (NSAIDs), which include, e.g., COX-2 inhibitors and sulphonanilides, may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary NSAIDs are detoprofen; diclofenac; diflunisal; etodolac; etoricoxib; fenoprofen; flunixin meglumine; flurbiprofen; ibuprofen; indomethacin; ketoprofen; lumiracoxib; meclofenameate; mefenamic acid; meloxicam; nabumeone; naproxen sodium; oxaprozin; parecoxib; piroxicam; sulindac; tolmetin; valdecoxib; celecoxib; rofecoxib; aspirin; choline salicylate; salsalte; acemetacin; alminoprofen; amfenac sodium; aminoprofen; anitrazafen; antrafenine; auranofin; bendazac lysinate; benzydamine; beprozin; broperamole; bufezolac; carprofen; cinmetacin; ciproquazone; clidanac; cloximate; dazidamine; deboxamet; delmetacin; detomidine; dexindoprofen; diacerein; di-fisalamine; difenpyramide; emorfazone; enfenamic acid; enolicam; epirizole; etersalate; etofenamate; fanetizole mesylate; fenclofenac; fenclorac; fendosal; fenflumizole; fentiazac; feprazone; floctafenine; flunoxaprofen; fluproquazone; fopirtoline; fosfosal; furcloprofen; furofenac; glucametacin; guaimesal; ibuproxam; isofezolac; isonixim; isoprofen; isoxepac; isoxicam; lefetamine HCl; leflunomide; lofemizole; lonazolac calcium; lotifazole; loxoprofen; lysin clonixinate; meseclazone, miroprofen; nabumetone; nictindole; nimesulide; orpanoxin; oxametacin; oxapadol; perisoxal citrate; pimeprofen; pimetacin; piproxen; pirazolac; pirfenidone; pirprofen; pranoprofen; proglumetacin maleate; proquazone; pyridoxiprofen; sudoxicam; suprofen; talmetacin; talniflumate; tenoxicam; thiazolinobutazone; thielavin B; tiaprofenic acid; tiaramide HCl; tiflamizole; timegadine; tioxaprofen; tolfenamic acid; tolpadol; tryptamid; ufenamate; zidometacin; and sodium and magnesium salicylate.
Leukotriene antagonists may also be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Leukotriene antagonists include zileuton; 5-lipoxygenase;
MK-886; FLAP; montelukast; acitazanolast; iralukast; montelukast; zafirlukast; pranlukast; and velukast.
Additional NSAIDs and leukotriene antagonists are described in EP
199543, GB 971700, BE 679678, BE 679271, BE 812772, and in U.S. Patent
Nos. 3,161,654, 3,337,570, 3,385,886, 4,859,692, 4,918,092, 4,939,279,
4,954,513, 5,143,931, 5,266,568, 5,266,713, 5,393,768, 5,462,954, 5,466,823, 5,817,684, 5,952,347, 6,797,723, and 7,074,826, hereby incorporated by reference. Proton Pump Inhibitors and Analogs or Derivatives Thereof
Proton pump inhibitors may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary proton pump inhibitors are omeprazole; lansoprazole; esomeprazole; pantoprazole; and rabeprazole.
Additional proton pump inhibitors are described in U.S. Patent Nos. 4,045,564, 4,255,431, 4,628,098, 4,634,710, 4,758,579, 4,806,549,4,806,550, 4,818,760, 4,839,365, 4,845,118, 4,871,734, 4,873,337, 4,956,366, 4,981,861, 5,045,552, 5,114,955, 5,149,702, 5,439,917, 5,554,631, 5,665,730, 5,677,302, 5,686,458, 5,693,818, 5,703,097, 5,750,531, 5,990,311, 5,952,504, 5,945,425, and 6,559, 167, and in PCT Publication Nos. WO 89/08104, WO 92/12969, WO 95/27714, WO 97/32854, WO 98/18784, WO 98/43968, and WO 98/54172, hereby incorporated by reference.
Channel Modulators and Analogs or Derivatives Thereof
Channel modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary channel modulators are A-53930A; AE-0047;
AGN-190604; AGN-190744; AH-1058; AHR-12742; AHR-16303B; AHR- 16462B; AIT-1 10; AIT-111 ; AJ-3941 ; AM-336; amlopidine (including S-(-),
R-(+), and racemic); anipamil; 2-APB; AP-1067; aranidipine; atosiban; azelnidipine; barnidipine; BAY K8644; Bay-t-7207; Bay-y-5959; Bay-z-4406;
BBR-2160; belfosdil; BIII-890-CL; bisaramil; BMS-181 102; BMS-188107;
BMY-4301 1 ; BRL-32872; buflomedil; capsaicin derivatives (e.g., TRPV); CD- 349; CD-832; CERM- 12816; CGP-28932; cilnidipine; dentiazem; clevidipine;
CNS-1067; CNS-1237; CNS-2103; CP-060S; CPC-301 ; CPC-317; CPU-
86017; D-2024; darodipine; DHP-218; diftiazem; diperdipine; dopropidil; dotarazine; dronedarone; DTZ-323; E-047/1 ; efonidipine; EGIS-7229; elgodipine, emopamil; etomoxir; F-0401 ; fantofarone; fasudil; FCE-24265; FCE-26262; FCE-27335; FCE-27892; FCE-28718; felodipine; FPL-64176;
FR-172516; FRG-8701 ; fumidipine; gliquidone; GS-386; icilin; iganidipine; ipenoxazone; isradipine; JTV-591 ; KP-840; KT-362; L-366682; lacidipine;
LAS-0538; LCB-2514; lemildipine; lercanidipine; leualacin, lifarizine; LOE-
908; lomerizine; lubeluzole; LY-042826; manidipine, McN-6186, mibefradil; monatepil; moricizine; MR-14134; N-3601 ; NCC-1048; nefiracetam; nexopamil; nifedipine; nifedipine; nifelan; nilvadipine; nimodipine; NNC-09-
0026; NPS-568; NS-638; NS-649; NS-696; NS-7; OPC-8490; Org-13061 ; Org-
30029; oxodipine; P-5; palonidipine; PCA-50922; PCA-50938; PCA-50941 ;
PD-029361; PD-157667; PD-158143; PD-176078; pranidipine; QX-314; ranolazine; RHG-2716; RingCap; Ro-11-2933; RS-5773; RU-43945; RWJ- 22108; RWJ-22726; RWJ-29009; RWJ-37868; S-12968; S-2150; S-312-d;
SANK-71996; SB-201823; SB-206284A; SB-23736; SD-3212; semotiadil;
SIB- 1281 ; siratiazem; SKFA-45675; SKF-96365; SKT-M-26; SL-34.0829; SL-
87.0495; SM-6586; SNX-124; SNX-236; SNX-239; SNX-325; SNX-482; SQ-
31727; SQ-33351 ; SQ-34399; SR-33805; TA-993; tamolarizine; TDN-345; temiverine; terodiline; TH-9229; TN-871 ;U-88999; U-92032; U-92798; UCL-
1439; UK-1656; UK-55444; UK-56593; UK-84149; verapamil; verelan; vexibinol; VUF-8929; WAY- 141520; XB-513; XT-044; Y-22516; YH-334;
YM- 1615-4; YM-430; Z-6568; ziconotide; ZM-224832; agitoxin; alinidine; charybdotoxin; chlorzoxazone; clotrimazole; dendrotoxin; diazoxide; iberiotoxin; minoxidil; pinacidil; repaglinide; tertiapin; tetracaine; and zatebradine hydrochloride.
Additional channel modulators are described in DE 2000339, DE
2011 126, EP 7293, DE 2014201, and in U.S. Patent Nos. 3,708,486, 3,740,395,
4,264,61 1, 4,902,694, 5,328,830, 5,965,696, 6,150,357, 6,462,059, 6,646,012, 6,872,741, 7,132,422, 7,151,180, 7,183,323, 7,208,527, 7,226,950, 7,368,467, and 7,429,618, hereby incorporated by reference.
Receptor Modulators and Analogs or Derivatives Thereof
Receptor modulators may be used as therapeutic agents in the compositions, methods, and kits of the invention in combination with additional agents. Exemplary receptor modulators are otilonium bromide, drotaverine, dextromethorphan, and hydrobromide (opioid receptor modulators); promethazine (histamine receptor modulator); securinine and diazepam (GABA receptor modulators); and nebivolol and phenoxylbenzamine (adrenergic receptor modulators). Additional receptor modulators are described in BE 621917 and in U.S.
Patent Nos. 2,530,451, 2,607,773, 2,676, 177, 3,371,085, 3,109,843, 3,136,815, 3,102,116, 3,536,723, 4,479,955, 6,100,259, 6,953,787, 7,045,540, 7,041,681, 7,166,593, 7,115,600, 7,489,359, 7,470,698, 7,432,283, 7,358,246, and 7,351,698, hereby incorporated by reference.
Additional therapeutic agents are listed in Tables 1, 2, and 3 and described herein. Amcinonide analogs are described in DE 2437847. Amlodipine besylate analogs are described in EP 89167 and U.S. Patent No. 4,572,909. Atorvastatin analogs are described in EP 409281 and U.S. Patent No. 5,273,995. Betamethasone analogs are described in U.S. Patent No.
3,053,865 and U.S. Patent No. 3,104,246. C6-Ceramide analogs are described in U.S. Patent No. 5,631,394. Chromomycin A3 analogs are described in JP 60 7842 and DE 1072775. Clobetasol analogs are described in DE 1902340 and U.S. Patent No. 3,721,687. Clofarabine analogs are described in U.S. Patent No. 6,680,382. Corticosterone analogs are described in U.S. Patent No.
2,676,904, U.S. Patent No. 2,166,877, U.S. Patent No. 2,341,250, U.S. Patent No. 2,671,752, and U.S. Patent No. 2,927, 108. Cycloheximide analogs are described in U.S. Patent No. 2,574,519, U.S. Patent No. 3,915,802, and U.S. Patent No. 3,915,803. Dactinomycin analogs are described in DE 1 172680. Desoximetasone analogs are described in FR 1296544, U.S. Patent No. 3,099,654, BE 614196, and U.S. Patent No. 3,232,839. Dexamethasone analogs are described in U.S. Patent No. 3,007,923, DE 1 113690, and GB 86951 1. Dichlorisone analogs are described in U.S. Patent No. 2,894,963. Doxorubicin analogs are described in ZA 68 02378, U.S. Patent No. 3,590,028, DE 1917874, U.S. Patent No. 4,012,448, BE 898506, and GB 2133005.
Fludarabine analogs are described in U.S. Patent No. 4,210,745 and U.S. Patent No. 4,357,324. Fludrocortisone analogs are described in U.S. Patent No. 2,957,013, GB 792224, and U.S. Patent No. 2,852,51 1. Flunisolide analogs are described in GB 933867, U.S. Patent No. 3,124,571, and U.S. Patent No. 3,126,375. Fluocinolone acetonide analogs are described in U.S. Patent No. 3,014,938 and U.S. Patent No. 3, 126,375. Fluocinonide analogs are described in GB 916996, U.S. Patent No. 3, 124,571, U.S. Patent No. 3,126,375, and U.S. Patent No. 3,197,469. Fluprednisolone analogs are described in DE 1079042, DE 1088953, and U.S. Patent No. 2,841,600. Fluticasone analogs are described in NL 81 00707 and U.S. Patent No. 4,335,121. Loteprednol etabonate analogs are described in BE 889563 and U.S. Patent No. 4,996,335. Melphalan analogs are described in U.S. Patent No. 3,032,584 and U.S. Patent No. 3,032,585. NKH 477 analogs are described in U.S. Patent No. 4,088,659, DE 2557784, and U.S. Patent No. 4,476,140. Perhexiline analogs are described in GB 1025578. Plicamycin analogs are described in HU 155679. Rimexolone analogs are described in NL 7300313 and U.S. Patent No. 3,947,478. Sulindac analogs are described in DE 2039426 and U.S. Patent No. 3,654,349. Tetrabenazine analogs are described in U.S. Patent No. 2,830,993. Trequinsin analogs are described in U.S. Patent No. 5,141,936. Triamcinolone analogs are described in U.S. Patent No. 2,789,118 and U.S. Patent No. 3,021,347. Triflupromazine analogs are described in GB 813861. Albendazole analogs are described in U.S. Patent No. 3,915,986. Amitriptyline analogs are described in BE 584061, GB 858187, GB 858188, and U.S. Patent No. 3,205,264. Amoxicillin analogs are described in GB 978178, U.S. Patent No. 3,192,198, DE 1942693, and GB 1241844. Bepridil analogs are described in DE 2310918, U.S. Patent No. 3,962,238, and DE 2802864. Bicalutamide analogs are described in EP 100172 and U.S. Patent No. 4,636,505. Butoconazole analogs are described in U.S. Patent No. 4,078,071. Chlorquinaldol analogs are described in U.S. Patent No. 2,41 1 ,670. Chlorothymol analogs are described in DE 905738. Chlorprothixene analogs are described in GB 829763 and U.S. Patent No. 3,046,283. Clemastine fumarate analogs are described in GB
942152. Clomipramine analogs are described in CH 371799 and U.S. Patent No. 3,467,650. Cloperastine analogs are described in GB 670622 and GB 1179945. Clopidogrel analogs are described in EP 99802, U.S. Patent No. 4,529,596, EP 281459, and U.S. Patent No. 4,847,265. Clorofene analogs are described in U.S. Patent No. 1,967,825 and DE 703955. Dienestrol analogs are described in U.S. Patent No. 2,464,203 and U.S. Patent No. 2,465,505.
Donepezil analogs are described in EP 296560 and U.S. Patent No. 4,895,841. Doxepin analogs are described in U.S. Patent No. 3,438,981, NL 6407758, BE 641498, and U.S. Patent No. 3,420,851. Ethinyl estradiol analogs are described in DE 702063, GB 516444, U.S. Patent No. 2,243,887, U.S. Patent No. 2,251,939, U.S. Patent No. 2,265,976, and U.S. Patent No. 2,267,257. Ezetimibe analogs are described in WO 95/08532 and U.S. Patent No. 5,767,115. Fenofibrate analogs are described in DE 2250327, DE 2003430, and U.S. Patent No. 4,058,552. Fenticlor analogs are described in DE 568944. Hydroxyzine analogs are described in U.S. Patent No. 2,899,436. Ibudilast analogs are described in DE 2315801 and U.S. Patent No. 3,850,941. Irsogladine analogs are described in DE 2506814 and U.S. Patent No. 3,966,728. Isradipine analogs are described in DE 2949491, U.S. Patent No. 4,466,972, and DE 3320616. Lansoprazole analogs are described in EP 174726 and U.S. Patent No. 4,628,098. Lindane analogs are described in U.S. Patent No. 2,218,148. Loratadine analogs are described in U.S. Patent No. 4,282,233. Miconazole analogs are described in DE 1940388 and U.S. Patent No. 3,717,655. Moricizine analogs are described in DE 2014201 and U.S. Patent No. 3,740,395. Nabumetone analogs are described in U.S. Patent No. 4,061,779 and DE 2442305. Nicardipine analogs are described in BE 81 1324 and U.S. Patent No. 3,985,758. Nimodipine analogs are described in DE 2117571, U.S. Patent No. 3,799,934, GB 2018134, and U.S. Patent No. 4,406,906. Nisoldipine analogs are described in DE 2549568 and U.S. Patent No. 4,154,839. Octyl methoxycinnamate analogs are described in U.S. Patent No. 4,713,473. Permethrin analogs are described in DE 2437882, DE 2544150, and U.S. Patent No. 4,1 13,968. Phenothiazine analogs are described in DE 25150, U.S. Patent No. 2,415,363, U.S. Patent No. 2,887,482, and U.S. Patent No. 3,000,887. Triclabendazole analogs are described in BE 865870 and U.S. Patent No. 4,197,307. Zafirlukast analogs are described in U.S. Patent No. 4,859,692 and EP 199543. Amiloride analogs are described in U.S. Patent No. 3,313,813 and BE 639386. Amiodarone analogs are described in U.S. Patent No. 3,248,401 and FR 1339389. Diltiazem analogs are described in U.S. Patent No. 4,552,695, DE 1805714, DE 3415035, and U.S. Patent No. 3,562,257. Gabapentin analogs are described in U.S. Patent No. 4,024,175 and DE 2460891. Ivermectin analogs are described in U.S. Patent No. 4,199,569 and JP Kokai 79 61198. Loperamide analogs are described in U.S. Patent No. 3,714,159 and FR 2100711. Neomycin analogs are described in U.S. Patent Nos. 2,799,620, 2,848,365, 3,108,996, 3,005,815, 3,022,228, and GB 945475. Nifedipine analogs are described in U.S. Patent No. 3,485,847 and ZA 68 01482. Flavoxate analogs are described in U.S. Patent Nos. 2,921,070 and 3,350,411. Cinnarizine analogs are described in U.S. Patent No. 2,882,271. Fendiline analogs are described in U.S. Patent No. 3,262,977 and BE 621300. Fluspirilene analogs are described in U.S. Patent No. 3,238,216 and BE 633914. Flunarizine analogs are described in U.S. Patent No. 3,773,939, DE 1929330, and FR 2014487. Lercanidipine analogs are described in U.S. Patent No. 4,705,797 and EP 153016. Tetracaine analogs are described in U.S. Patent No. 1,889,645, GB 815144, and U.S. Patent No. 3,272,700. Methadone analogs are described in U.S. Patent Nos. 2,644,010 and 2,983,757. Cilnidipine analogs are described in U.S. Patent No. 4,672,068 and EP 161877. Penfluridol analogs are described in U.S. Patent No. 3,575,990 and DE 2040231. Phloretin analogs are described in U.S. Patent No. 2,789,995. Mibefradil analogs are described in U.S. Patent No. 4,808,605 and EP 268148. Letrazole analogs are described in U.S. Patent No. 4,978,672 and EP 236940. Medrysone analogs are described in U.S. Patent Nos. 2,864,837 and 2,968,655. Naltrexone analogs are described in U.S. Patent No. 3,332,950. Phenazopyridine analogs are described in U.S. Patent Nos. 1,680,108, 1,680, 109, 1,680, 1 10, and 1,680,1 1 1. Riluzole analogs are described in U.S. Patent No. 4,370,338, EP 50551 , and EP 558861. Risperidone analogs are described in U.S. Patent No. 4,804,663 and EP 196132. Teniposide analogs are described in U.S. Patent No. 3,524,844 and ZA 66 07585. Thonzonium analogs are described in U.S. Patent No. 2,742,470. Flunixin analogs are described in U.S. Patent Nos. 3,839,344 and 3,337,570, BE 679271, and BE 812772. Diazepam analogs are described in U.S. Patent Nos. 3,371,085, 3,109,843, 3,136,815, and 3,102,116. Pramipexole analogs are described in U.S. Patent No. 4,886,821 and EP 186087. Rosiglitazone analogs are described in U.S. Patent No. 5,002,953 and EP 306228. Ciclesonide analogs are described in U.S. Patent No. 5,482,934 and DE 4129535. Auranofin analogs are described in U.S. Patent No. 3,635,945 and DE 2051495. Clofoctol analogs are described in U.S. Patent No. 3,830,852. Clotrimazole analogs are described in U.S. Patent No. 3,705,172 and ZA 68 05392. Cyproheptadine analogs are described in U.S. Patent No. 3,014,91 1. Dichlorophen analogs are described in U.S. Patent No. 2,334,408. Dienestrol analogs are described in U.S. Patent Nos. 2,464,203 and 2,465,505. Econazole analogs are described in U.S. Patent No. 3,717,655 and DE 1940388. Haloprogin analogs are described in U.S. Patent No. 3,322,813 and JP 64 19791. Hexachlorophene analogs are described in U.S. Patent Nos. 2,250,480, 2,435,593, and 2,812,365. Lomerizine analogs are described in U.S. Patent No. 4,663,325 and EP 159566. Naftifine analogs are described in U.S. Patent No. 4,282,251, BE 853976, and ES 504432. Naltrexone analogs are described in U.S. Patent No. 3,332,950. Pimozide analogs are described in FR M3695. Rabeprazole analogs are described in U.S. Patent No. 5,045,552 and EP 268956. Tioconazole analogs are described in U.S. Patent No. 4,062,966 and BE 841309. Amprenavir analogs are described in U.S. Patent No. 5,585,397 and WO 94/05639. 10- Deacetylbaccatine III analogs are described in U.S. Patent No. 4,814,470 and EP 253738. Captopril analogs are described in U.S. Patent Nos. 4,046,889 and 4,105,776, as well as in DE 2703828. Sirolimus analogs are described in U.S. Patent Nos. 3,929,992, 5,672,605, 5,373,014, 5,023,264, and 5,378,836, as well as in DE 2347682. Carteolol analogs are described in U.S. Patent No.
3,910,924 and DE 2302027. Deflazacort analogs are described in U.S. Patent No. 3,436,389, BE 679820, and GB 1077393. Epoxomicin analogs are described in U.S. Patent No. 5,071,957 and EP 411660. Gusperimus analogs are described in U.S. Patent Nos. 4,518,532 and 4,525,299, as well as in BE 894651 and EP 94632. Bimoclomol analogs are described in U.S. Patent No. 6,649,628. Desonide analogs are described in U.S. Patent Nos. 2,990,401, 3,536,586, and 3,549,498. Celecoxin analogs are described in U.S. Patent No. 5,466,823 and WO 95/15316. Budesonide analogs are described in U.S. Patent No. 3,929,768 and DE 2323215. Diacerein analogs are described in U.S. Patent Nos. 4,244,968 and 4,346,103, as well as DE 271 1493 and JP Kokai 83 225015. Rolipram analogs are described in U.S. Patent No. 4,193,926 and BE 826923. Biothionol analogs are described in DE 583055 and U.S. Patent No. 2,849,494. Epirubicin analogs are described in DE 2510866, BE 898506, GB 2133005, and U.S. Patent No. 4,058,519. Trifluoperazine analogs are described in GB 813861 and U.S. Patent No. 2,921,069. Nortriptyline analogs are described in NL 6408512 and U.S. Patent Nos. 3,442,949 and 3,922,305. Tamoxifen analogs are described in BE 637389, BE 678807, and in U.S. Patent Nos. 4,536,516, 6,096,874, 6,576,645, 6,875,775, and 5,807,899. Nebivolol analogs are described in EP 145067 and U.S. Patent No. 4,654,362. Pranlukast analogs are described in EP 173516 and U.S. Patent No. 4,780, 469. Emetine analogs are described in U.S. Patent No. 3, 102,118. Diphenoxylate hydrochloride analogs are described in U.S. Patent No. 2,898,340. Gestodene analogs are described in BE 847090 and U.S. Patent No. 4,081,537. Diazolidinyl urea analogs are described in WO 81/00566 and U.S. Patent No. 4,271,176. Oxymethurea analogs are described in U.S. Patent Nos. 1,863,426 and 2,436,355. Chloramphenicol analogs are described in GB 795131, GB 796901, and in U.S. Patent Nos. 2,483,871, 2,483,884, 2,483,892, and 2,839,577. Disopyramide analogs are described in BE 617730 and U.S. Patent No. 3,225,054. Ethaverine analogs are described in U.S. Patent Nos. 1,962,224 and 2,971,888. Malotilate analogs are described in BE 834631 and U.S. Patent Nos. 4,035,387 and 4,327,223. Exalamide analogs are described in GB
726786. Cephapirin analogs are described in ZA 67 07783 and in U.S. Patent Nos. 3,422,100, 3,503,967, and 3,578,661. Dioxybenzone analogs are described in U.S. Patent No. 2,853,521. Efavirenz analogs are described in EP 582455 and U.S. Patent No. 5,519,021. Saperconazole analogs are described in EP 283992 and U.S. Patent No. 4,916,134. Securine analogs are described in GB 1169471 and U.S. Patent No. 3,538,103. Benproperine phosphate analogs are described in GB 914008 and U.S. Patent No. 3,117,059. Epoxomicin analogs are described in EP 411660 and U.S. Patent No. 5,071,957. Fenipentol analogs are described in GB 915815 and U.S. Patent No. 3,084,100. Phenoxybenzamine analogs are described in U.S. Patent No. 2,599,000. Telithromycin analogs are described in EP 680967 and U.S. Patent No.
5,635,485. Domperidone analogs are described in DE 2632870 and U.S. Patent No. 4,066,772. Vigabatrin analogs are described in U.S. Patent No. 3,960,927. Argatroban analogs are described in U.S. Patent No. 4,258,192. Mofebutazone analogs are described in GB 839057. MS-275 analogs are described in Japanese Patent Publication Hei No. 10-152462 and U.S. Patent No. 7,056,883. Sangivamycin analogs are described in U.S. Patent No. 3,423,398. Forskolin analogs are described in DE 2557784 and in U.S. Patent Nos. 4,088,659 and 4,476,140. Padimate analogs are described in GB 1162337, FR 1566396, and U.S. Patent No. 3,403,207. N-methyl-paroxetine analogs are described in U.S. Patent No. 4,007, 196 and WO 2007/034270. Chenodeoxycholic acid analogs are described in U.S. Patent No. 4,425,273. Sodium phenylbutyrate analogs are described in U.S. Patent Nos. 4,457,942 and 5,605,930. 2- Methoxyestradiol analogs are described in WO 01/014405 and U.S. Patent No. 7,371,741. AL-438 analogs are described in U.S. Patent Application Publication Nos. 2007/0213296 and 2007/0265296. Corosolic acid analogs are described in U.S. Patent Nos. 6,893,627 and 7,071,229. Daptomycin analogs are described in U.S. Patent Nos. 4,885,243 and 6,750,199. GGTI analogs are described in U.S. Patent No. 5,965,539. Vatalanib analogs are described in U.S. Patent Nos. 6,258,812, 6,514,974, 6,710,047, and 7,417,055. HC toxin analogs are described in U.S. Patent Nos. 4,735,651 and 6,428,983. Histone deacetylase inhibitor (class III) analogs are described in U.S. Patent Nos. 6,174,905, 6,541,661, and 6,897,220. Homoharringtonine analogs are described in U.S. Patent Nos. 4,152,214 and 4,783,454. 2-APB analogs are described in U.S. Patent No. 7,217,701. AG-879 analogs are described in U.S. Patent No. 6,552,066. Thiethylperazine maleate analogs are described in U.S. Patent Application Publication No. 2006/0148827. Lomeguatrib analogs are described in U.S. Patent No. 6,043,228. Viburnine analogs are described in U.S. Patent Application Publication No. 2005/0112215. Magnesium lactate analogs are described in U.S. Patent Nos. 4,282,385 and 4,737,314. APWAGl analogs are described in U.S. Patent Application Publication No. 2006/0252045. HU-210 analogs are described in U.S. Patent Nos. 5,284,867, 6,096,740, and 7,297,796. Icilin analogs are described in U.S. Patent No. 3,821,221. 6-Iodonordihydro-capsaicin analogs are described in U.S. Patent Nos. 4,313,958, 4,401,663, 4,424,206, 4,443,473, 4,498,848, and 4,599,342. TN- 16 analogs are described in U.S. Patent No. 6,693,125. Farnesyl transferase inhibitors and their analogs are described in U.S. Patent Nos.
5,420,245, 5,843,941, 5,874,442, 6,013,662, 6,225,322, and 7,323,484. JNK inhibitors and their analogs are described in U.S. Patent Nos. 6,642,227, 7,084,159, 7,199,124, 7,211,594, 7,402,595, and 7,417,058. RG-14620 analogs are described in U.S. Patent Nos. 6,225,346, 6,524,832, and 6,552,066. Clove oil analogs are described in U.S. Patent No. 4,217,371. GTP-14564 analogs are described in PCT Publication No. WO 06/135639 and in U.S. Patent Application Publication Nos. 2005/0165024, 2005/0171171, and 2006/0281700. BML-257 analogs are described in U.S. Patent No. 6,288,065. 2-Amino-5-chlorobenzophenone analogs are described in U.S. Patent Nos. 2,773,903, 2,853,522, 2,853,523, 2,928,878, 3,941,802, and 4,000,151.
Apigenin analogs are described in U.S. Patent Nos. 4,617,293, 4,774,229, and 5,756,538. 5-Methyl-2-(3-phenyl-lH-pyrazole-5-yl)phenol analogs are described in U.S. Patent No. 4,851,410. DAPH analogs are described in U.S. Patent No. 5,491,144, 5,663,336, 5,821,246, and 5,955,464. SU-4312 analogs are described in U.S. Patent Nos. 5,792,783, 5,834,504, 5,883,1 13, 5,883,116, and 6,906,093. Chloro(trimethylphosphine) gold (I) analogs are described in U.S. Patent No. 3,883,546. Cetylpyridinium chloride analogs are described in U.S. Patent No. 4,154,744. Amsacrine analogs are described in U.S. Patent Nos. 5,604,237 and 6,207,673. Ro 48-8071 analogs are described in U.S. Patent No. 6,964,974. U 18666A analogs are described in U.S. Patent No. 5,998,433. Suxamethonium iodide analogs are described in U.S. Patent No. 5,418,226. Carboxymethylcellulose analogs are described in U.S. Patent Nos. 3,959,080, 4,988,806, and 5,023,246. Doripenem analogs are described in PCT Publication No. WO 06/117763 and in U.S. Patent Nos. 4,683,301, 4,710,568, 4,880,922, 5,192,758, 5,532,261, 5,559,224, 6,277,843, 6,310,056, 6,458,780, 6,677,331, and 7,001,897. Nictotine analogs are described in U.S. Patent Nos. 5,015,741, 5,138,062, and 6,747,156. Ruthenium red analogs are described in Matlib et al. (J. Biol. Chem. 273: 10223-10231, 1998). Nedaplatin analogs are described in U.S. Patent Nos. 4,177,263, 6,534,096, and 6,548,541. N-(n- nonyl) deoxynojirimycin analogs are described in EP 0012278 and in U.S. Patent Nos. 4,611,058 and 4,806,650. Aurintricarboxylic acid analogs are described in U.S. Patent Nos. 4,007,270, 4,1 13,879, and 4,880,788. L-741,626 analogs are described in U.S. Patent Nos. 4,454,150 and 5,302,599. TO- 901317 analogs are described in U.S. Patent Nos. 6,316,503 6,924,311, and 7,365,085. trøns-4-Iodo,4'-boranyl-chalcone analogs are described in U.S. Patent Application Publication No. 2005/0176988. Zinc protoporphyrin analogs are described in U.S. Patent Nos. 4,831,024 and 5,081,115. All of these references are hereby incorporated by reference.
Additional Therapeutic Agents If desired, the patient may also receive additional therapeutic regimens.
For example, therapeutic agents may be administered with the agent or agents described herein at concentrations known to be effective for such therapeutic agents. Particularly useful agents include those that treat or ameliorate symptoms of a disorder associated with a defect in the CFTR gene or protein. Such agents include, for example, those that thin mucosal obstructions, treat bacterial infections, reduce inflammation, and open airway passages. Exemplary agents are known therapeutics, ion-channel modulators, antiinflammatory agents, antimicrobial agents, analgesics, anesthetics, or bronchodilators.
Known Therapeutics for the Treatment of a Disorder Associated with a Defect of the CFTR Gene or Protein
Any suitable therapeutic regimen known to treat or ameliorate the disorder may be administered. Suitable agents include, e.g., 4-[4-oxo-2-thioxo- 3-(3-trifluoromethyl-phenyl)-thiazolidin-5-ylidenemethyl]-benzoic acid; (naphthalen-2-ylamino)-acetic acid (3,5-dibromo-2,4,-dihydroxy-benzylidene)- hydrazide; diarylsulfonylurea; 4-methyl-2-(5-phenyl-lH-pyrazol-3-yl)-phenol; 2-[(2-lH-indol-3-yl-acetyl)-methyl-amino]-N-(4-isopropyl-phenyl)-2-phenyl- acetamide; 6-(ethyl-phenyl-sulfonyl)-4-oxo- 1 ,4-dihydro-quinoline-3-carboxylic acid 2-methoxy-benzylamide; l-(3-chlorophenyl)-5-trifluoromethyl-3- hydrobenzimidazol-2-one; 2-(2-chloro-benzoylamino)-4,5,6,7-tetrahydro- benzo[b]thiophene-3-carboxylic acid amide; 5,7,dihydroxy-3-(4-hydroxy- phenyl)-chroman-4-one; 1 -(5-chloro-2-hydroxy-pheny l)-5-trifluoromethyl- 1,3- dihydro-benzoimidazol-2-one; 4-(4-oxo-4H-benzo[h]chromen-2-yl)- pyridinium; bisulfate 3 -but-3-ynyl-5-methoxy-l -phenyl- lH-pyrazole-4- carbaldehyde; 3-(2-benzyloxy-phenyl)-5-chloromethyl-isoxazole; 6-(1H- benzomidazol-2-ylsulfanylmethyl)-2-(6-methoxy-4-methyl-quinazolin-2- ylamino)-pyrimidin-4-ol; 2-{ l-[4-(4-chloro-benzensulfonyl)-piperazin-l-yl]- ethyl}-4-piperidin-l-yl-quinazoline; 4-cyclohexyloxy-2-{ l-[4-(4-methoxy- benzensulfonyl)-piperazin-l-yl]-ethyl}-quinazoline; N-[2-(5-chloro-2- methoxy-phenylamino)-4'-methyl-[4,5']bithiazolyl-2'-yl]-benzamide; and N-(4- bromophenyl)-4-methylquinolin-2-amine.
Ion-Channel Modulators
Any suitable ion-channel modulator may be administered. Suitable ion- channel modulators include, e.g., amiloride; 2-APB; BAY K8644; calciseptine; cilnidipine; diltiazem; flunarizine; FPL-64176; gabapentin; kuratoxin; SDZ- 202; tetrandrine; fipronil; IAA-94; 5-nitro-(3-phenylpropylamino) benzoic acid; batrachotoxin; bupivacaine; kavain; monensin; palytoxin; PD-85639; QX- 314; riluzole; and veratridine.
Anti-Inflammatory Agents
Any suitable anti-inflammatory agent may be administered. Suitable anti-inflammatory agents include, e.g., non-steroidal anti-inflammatory drugs (e.g., ibuprofen or tacrolimus), cyclooxygenase-2-specific inhibitors (e.g., rofecoxib (Vioxx®) and celecoxib (Celebrex®)), topical glucocorticoid agents, and specific cytokines directed at T lymphocyte function. Additional suitable anti-inflammatory agents include flubiprofen, diclofenac, and ketarolac. Antiinflammatory concentrations known to be effective may be used. For example, ibuprofen may be present in the composition at concentrations sufficient to deliver between 25-800 mg per day to the patient. Exemplary anti- inflammatory agents are listed in, e.g., U.S. Patent Nos. 7,112,578 and 7,199,1 19, hereby incorporated by reference.
Antimicrobial Agents
Any of the many known antimicrobial agents can be used in the compositions described herein at concentrations generally used for these agents. Antimicrobial agents include, e.g., antibacterial, anti-fungal, and antiviral agents.
Examples of antibacterial agents (antibiotics) are penicillins (e.g., penicillin G, ampicillin, methicillin, oxacillin, and amoxicillin), cephalosporins (e.g., cefadroxil, ceforanid, cefotaxime, and ceftriaxone), tetracyclines (e.g., doxycycline, minocycline, and tetracycline), aminoglycosides (e.g., amikacin, gentamycin, kanamycin, neomycin, streptomycin, and tobramycin), macrolides (e.g., azithromycin, clarithromycin, and erythromycin), fluoroquinolones (e.g., ciprofloxacin, lomefloxacin, moxifloxacin, and norfloxacin), and other antibiotics including chloramphenicol, clindamycin, cycloserine, isoniazid, rifampin, and vancomycin. Exemplary antimicrobial agents are described in, e.g., U.S. Patent Nos. 6,830,745 and 7,056,917, hereby incorporated by reference.
Anti-viral agents are substances capable of destroying or suppressing the replication of viruses. Examples of antiviral agents are 1-β-D-ribofuranosyl- 1 ,2,4-triazole-3 carboxamide (ribavirin), 9-2-hydroxy-ethoxy methylguanine, adamantanamine, 5-iodo-2'-deoxyuridine, trifluorothymidine, interferon, adenine arabinoside, protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, attachment and adsorption inhibitors, and nucleoside analogues such as acyclovir, penciclovir, valacyclovir, and ganciclovir. Exemplary anti-viral agents are described in, e.g., U.S. Patent Nos. 6,093,550 and 6,894,033.
Anti-fungal agents include both fungicidal and fungistatic agents, e.g., amphotericin B, butylparaben, clindamycin, econaxole, fluconazole, flucytosine, griseofulvin, nystatin, and ketoconazole. Exemplary anti-fungal agents are described in, e.g., U.S. Patent Nos. 5,627,153 and 7,125,842, hereby incorporated by reference.
Analgesics and Anesthetics
Any of the commonly used topical analgesics and anesthetics can be used as therapeutic agents in the invention. Examples of useful anesthetics are procaine, lidocaine, tetracaine, dibucaine, benzocaine, p-buthylaminobenzoic acid 2-(diethylamino) ethyl ester HCl, mepivacaine, piperocaine, and dyclonine. Exemplary anesthetics are listed in, e.g., U.S. Patent Nos. 6,562,363 and 6,569,839, hereby incorporated by reference. Analgesics include opioids such as, e.g., morphine, codeine, hydrocodone, and oxycodone. Any of these analgesics may also be co- formulated with other compounds having analgesic or anti-inflammatory properties, such as acetaminophen, aspirin, codeine, naproxen, and ibuprofen. Exemplary analgesics are listed in, e.g., U.S. Patent Nos. 6,869,974 and 7,202,259, hereby incorporated by reference. Bronchodilators
Any commonly used bronchodilator can be used as a therapeutic agent in the invention described herein. Examples of useful bronchodilators include, e.g., pirbuterol, epinephrine, albuterol, salbutamol, salmeterol, or levalbuterol. Exemplary bronchodilators are described in, e.g., U.S. Patent Nos. 4,489,078, 4,591,588, 4,734,413, 6,299,863, and 6,555,583, hereby incorporated by reference.
If more than one agent is employed, therapeutic agents may be delivered separately or may be admixed into a single formulation. When agents are present in different pharmaceutical compositions, different routes of administration may be employed. Routes of administration for the various embodiments include, but are not limited to, topical, transdermal, and systemic administration (e.g., intravenous, intramuscular, subcutaneous, inhalation, rectal, buccal, vaginal, intraperitoneal, intraarticular, ophthalmic or oral administration). As used herein, "systemic administration" refers to all non- dermal routes of administration, and specifically excludes topical and transdermal routes of administration. Desirably, the agent of the invention and additional therapeutic agents are administered within at least 1, 2, 4, 6, 10, 12, 18, 24 hours, 3 days, 7 days, 14 days, or 28 days apart. The dosage and frequency of administration of each component of the combination can be controlled independently. For example, one compound may be administered three times per day, while the second compound may be administered once per day. Combination therapy may be given in on-and-off cycles that include rest periods so that the patient's body has a chance to recover from any as yet unforeseen side effects. The compounds may also be formulated together such that one administration delivers both compounds. Optionally, any of the agents of the combination may be administered in a low dosage or in a high dosage, each of which is defined herein. The therapeutic agents of the invention may be admixed with additional active or inert ingredients, e.g., in conventional pharmaceutically acceptable carriers. A pharmaceutical carrier can be any compatible, non-toxic substance suitable for the administration of the compositions of the present invention to a mammal. Pharmaceutically acceptable carriers include, for example, water, saline, buffers and other compounds described, for example, in the Merck Index, Merck & Co., Rahway, New Jersey. Slow release formulation or a slow release apparatus may be also be used for continuous administration.
In addition to the administration of therapeutic agents, the additional therapeutic regimen may involve, e.g., gene therapy, lung transplantation, or a modification to the lifestyle of the patient being treated. Such lifestyle changes may be helpful to control the disorder and include weight loss, physical exercise, diet control, reduction in alcohol intake, or reduction in smoking.
Conjugates and Linkers
If desired, the drugs used in any of the combinations described herein may be covalently attached to one another to form a conjugate of formula XXX.
(A)-(L)-(B) (XXX)
In formula XXX, (A) is a compound listed in, e.g., Table 1, Table 2, or
Table 3 covalently tethered via a linker (L) to (B), a compound of, e.g., Table 1, Table 2, or Table 3.
Conjugates of the invention can be administered to a subject by any route and for the treatment of any disease described herein. The conjugates of the invention can be prodrugs, releasing drug (A) and drug (B) upon, for example, cleavage of the conjugate by intracellular and extracellular enzymes (e.g., amidases, esterases, and phosphatases). The conjugates of the invention can also be designed to largely remain intact in vivo, resisting cleavage by intracellular and extracellular enzymes. The degradation of the conjugate in vivo can be controlled by the design of linker (L) and the covalent bonds formed with drug (A) and drug (B) during the synthesis of the conjugate. Conjugates can be prepared using techniques familiar to those skilled in the art. For example, the conjugates can be prepared using the methods disclosed in G. Hermanson, Bioconjugate Techniques, Academic Press, Inc., 1996. The synthesis of conjugates may involve the selective protection and deprotection of alcohols, amines, ketones, sulfhydryls or carboxyl functional groups of drug (A), the linker, and/or drug (B). For example, commonly used protecting groups for amines include carbamates, such as tert-butyl, benzyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 9-fluorenylmethyl, allyl, and m- nitrophenyl. Other commonly used protecting groups for amines include amides, such as formamides, acetamides, trifluoroacetamides, sulfonamides, trifluoromethanesulfonyl amides, trimethylsilylethanesulfonamides, and tert- butylsulfonyl amides. Examples of commonly used protecting groups for carboxyls include esters, such as methyl, ethyl,
Figure imgf000058_0001
9-fluorenylmethyl, 2- (trimethylsilyl)ethoxy methyl, benzyl, diphenylmethyl, O-nitrobenzyl, ortho- esters, and halo-esters. Examples of commonly used protecting groups for alcohols include ethers, such as methyl, methoxymethyl, methoxyethoxymethyl, methylthiomethyl, benzyloxymethyl, tetrahydropyranyl, ethoxyethyl, benzyl, 2-napthylmethyl, O-nitrobenzyl, P- nitrobenzyl, P-methoxybenzyl, 9-phenylxanthyl, trityl (including methoxy- trityls), and silyl ethers. Examples of commonly used protecting groups for sulfhydryls include many of the same protecting groups used for hydroxyls. In addition, sulfhydryls can be protected in a reduced form (e.g., as disulfides) or an oxidized form (e.g., as sulfonic acids, sulfonic esters, or sulfonic amides). Protecting groups can be chosen such that selective conditions (e.g., acidic conditions, basic conditions, catalysis by a nucleophile, catalysis by a Lewis acid, or hydrogenation) are required to remove each, exclusive of other protecting groups in a molecule. The conditions required for the addition of protecting groups to amine, alcohol, sulfhydryl, and carboxyl functionalities and the conditions required for their removal are provided in detail in T. W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis (2nd Ed.), John Wiley & Sons, 1991 and P.J. Kocienski, Protecting Groups, Georg Thieme Verlag, 1994. Additional synthetic details are provided below.
The linker component of the invention is, at its simplest, a bond between drug (A) and drug (B), but typically provides a linear, cyclic, or branched molecular skeleton having pendant groups covalently linking drug (A) to drug (B).
Thus, linking of drug (A) to drug (B) is achieved by covalent means, involving bond formation with one or more functional groups located on drug (A) and drug (B). Examples of chemically reactive functional groups which may be employed for this purpose include, without limitation, amino, hydroxyl, sulfhydryl, carboxyl, carbonyl, carbohydrate groups, vicinal diols, thioethers, 2-aminoalcohols, 2-aminothiols, guanidinyl, imidazolyl, and phenolic groups. The covalent linking of drug (A) and drug (B) may be effected using a linker, which contains reactive moieties capable of reaction with such functional groups present in drug (A) and drug (B). For example, an amine group of drug (A) may react with a carboxyl group of the linker, or an activated derivative thereof, resulting in the formation of an amide linking the two.
Examples of moieties capable of reaction with sulfhydryl groups include α-haloacetyl compounds of the type XCH2CO- (where X=Br, Cl or I), which show particular reactivity for sulfhydryl groups, but which can also be used to modify imidazolyl, thioether, phenol, and amino groups as described by Gurd, Methods Enzymol. 1 1 :532 (1967). N-Maleimide derivatives are also considered selective towards sulfhydryl groups, but may additionally be useful in coupling to amino groups under certain conditions. Reagents such as 2- iminothiolane (Traut et al., Biochemistry 12:3266 (1973)), which introduce a thiol group through conversion of an amino group, may be considered as sulfhydryl reagents if linking occurs through the formation of disulphide bridges.
Examples of reactive moieties capable of reaction with amino groups include, for example, alkylating and acylating agents. Representative alkylating agents include: (i) α-haloacetyl compounds, which show specificity towards amino groups in the absence of reactive thiol groups and are of the type XCH2CO- (where X=Cl, Br or I), for example, as described by Wong, Biochemistry 24:5337 (1979); (ii) N-maleimide derivatives, which may react with amino groups either through a Michael type reaction or through acylation by addition to the ring carbonyl group, for example, as described by Smyth et al., JAm Chem Soc. 82:4600 (1960) and Biochem J. 91 :589 (1964);
(iii) aryl halides such as reactive nitrohaloaromatic compounds; (iv) alkyl halides, as described, for example, by McKenzie et al., J
Protein Chem. 7:581 (1988);
(v) aldehydes and ketones capable of Schiff s base formation with amino groups, the adducts formed usually being stabilized through reduction to give a stable amine; (vi) epoxide derivatives such as epichlorohydrin and bisoxiranes, which may react with amino, sulfhydryl, or phenolic hydroxyl groups;
(vii) chlorine-containing derivatives of s-triazines, which are very reactive towards nucleophiles such as amino, sufhydryl, and hydroxyl groups;
(viii) aziridines based on s-triazine compounds detailed above, e.g., as described by Ross, J Adv Cancer Res. 2: 1 (1954), which react with nucleophiles such as amino groups by ring opening;
(ix) squaric acid diethyl esters as described by Tietze, Chem Ber. 124: 1215 (1991); and
(x) α-haloalkyl ethers, which are more reactive alkylating agents than normal alkyl halides because of the activation caused by the ether oxygen atom, as described by Benneche et al., Eur J Med Chem. 28:463 (1993).
Representative amino-reactive acylating agents include:
(i) isocyanates and isothiocyanates, particularly aromatic derivatives, which form stable urea and thiourea derivatives respectively; (ii) sulfonyl chlorides, which have been described by Herzig et al.,
Biopolymers 2:349 (1964); (iii) acid halides;
(iv) active esters such as nitrophenylesters or N-hydroxysuccinimidyl esters;
(v) acid anhydrides such as mixed, symmetrical, or N- carboxy anhydrides;
(vi) other useful reagents for amide bond formation, for example, as described by M. Bodansky, Principles of Peptide Synthesis, Springer- Verlag, 1984;
(vii) acylazides, e.g. wherein the azide group is generated from a preformed hydrazide derivative using sodium nitrite, as described by Wetz et al., Anal Biochem. 58:347 (1974); and
(viii) imidoesters, which form stable amidines on reaction with amino groups, for example, as described by Hunter and Ludwig, J Am Chem Soc. 84:3491 (1962). Aldehydes and ketones may be reacted with amines to form Schiff s bases, which may advantageously be stabilized through reductive amination. Alkoxylamino moieties readily react with ketones and aldehydes to produce stable alkoxamines, for example, as described by Webb et al., in Bioconjugate Chem. 1 :96 (1990). Examples of reactive moieties capable of reaction with carboxy 1 groups include diazo compounds such as diazoacetate esters and diazoacetamides, which react with high specificity to generate ester groups, for example, as described by Herriot, Adv Protein Chem. 3: 169 (1947). Carboxyl modifying reagents such as carbodiimides, which react through O-acylurea formation followed by amide bond formation, may also be employed.
It will be appreciated that functional groups in drug (A) and/or drug (B) may, if desired, be converted to other functional groups prior to reaction, for example, to confer additional reactivity or selectivity. Examples of methods useful for this purpose include conversion of amines to carboxyls using reagents such as dicarboxylic anhydrides; conversion of amines to thiols using reagents such as N-acetylhomocysteine thiolactone, S-acetylmercaptosuccinic anhydride, 2-iminothiolane, or thiol-containing succinimidyl derivatives; conversion of thiols to carboxyls using reagents such as α -haloacetates; conversion of thiols to amines using reagents such as ethylenimine or 2- bromoethylamine; conversion of carboxyls to amines using reagents such as carbodiimides followed by diamines; and conversion of alcohols to thiols using reagents such as tosyl chloride followed by transesterification with thioacetate and hydrolysis to the thiol with sodium acetate.
So-called zero-length linkers, involving direct covalent joining of a reactive chemical group of drug (A) with a reactive chemical group of drug (B) without introducing additional linking material may, if desired, be used in accordance with the invention.
Most commonly, however, the linker will include two or more reactive moieties, as described above, connected by a spacer element. The presence of such a spacer permits bifunctional linkers to react with specific functional groups within drug (A) and drug (B), resulting in a covalent linkage between the two. The reactive moieties in a linker may be the same (homobi functional linker) or different (heterobifunctional linker, or, where several dissimilar reactive moieties are present, heteromultifunctional linker), providing a diversity of potential reagents that may bring about covalent attachment between drug (A) and drug (B).
Spacer elements in the linker typically consist of linear or branched chains and may include a C^10 alkyl, C2_i0 alkenyl, C2-io alkynyl, C2-β heterocyclyl, C6-I2 aryl, C7_14 alkaryl, C3_io alkheterocyclyl, or C1_1o heteroalkyl. In some instances, the linker is described by formula (XXXI):
G1-(Zl)0-(Y1)u-(Z2)s-(R3o)-(Z3)t-(Y2)v-(Z4)p-G2 (XXXI)
In formula (XXXI), G is a bond between drug (A) and the linker; G is a bond between the linker and drug (B); Z1, Z2, Z3, and Z4 each, independently, is selected from O, S, and NR31; R3 ] is hydrogen, C]_4 alkyl, C2_4 alkenyl, C2^ alkynyl, C2_6 heterocyclyl, C^-n aryl, C7_i4 alkaryl, C3_io alkheterocyclyl, or Ci_ 7 heteroalkyl; Y1 and Y2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; o, p, s, t, u, and v are each, independently, 0 or 1 ; and R30 is a Ci_10 alkyl, C2_io alkenyl, C2_10 alkynyl, C2_6 heterocyclyl, C^12 aryl, C7_14 alkaryl, C3_10 alkheterocyclyl, or C1-I0 heteroalkyl, or a chemical bond linking G]-(Z])0- (YX-(Z2X- to -(Z3)t-(Y2)V-(Z4)P-G2.
Examples of homobifunctional linkers useful in the preparation of conjugates of the invention include, without limitation, diamines and diols selected from ethylenediamine, propylenediamine and hexamethylenediamine, ethylene glycol, diethylene glycol, propylene glycol, 1 ,4-butanediol, 1 ,6- hexanediol, cyclohexanediol, and polycaprolactone diol.
Formulation Any of the agents employed according to the present invention may be contained in any appropriate amount in any suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition. The composition may be provided in a dosage form that is, e.g., suitable for the oral, parenteral (e.g., intravenous or intramuscular), rectal, cutaneous, nasal, vaginal, inhalant, skin (patch), or ocular administration route. Thus, the composition may be in the form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels (e.g., hydrogels), pastes, ointments, creams, plasters, drenches, osmotic delivery devices, suppositories, enemas, injectables, implants, sprays, or aerosols. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, 20th edition, 2000, ed. A.R. Gennaro, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York). For intranasal administration or administration by inhalation, the compounds of the invention may be delivered in the form of, e.g., a solution or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
If more than one agent is employed, each agent may be formulated in a variety of ways that are known in the art. Desirably, the agents are formulated together for the simultaneous or near simultaneous administration of the agents. Such co-formulated compositions can include the two agents formulated together in the same, e.g., pill, capsule, or liquid. It is to be understood that, when referring to the formulation of such combinations, the formulation technology employed is also useful for the formulation of the individual agents of the combination, as well as other combinations of the invention. By using different formulation strategies for different agents, the pharmacokinetic profiles for each agent can be suitably matched.
The individually or separately formulated agents can be packaged together as a kit. Non-limiting examples include kits that contain, e.g., two pills, a pill and a powder, a suppository and a liquid in a vial, or two topical creams. The kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized intravenous delivery systems, or inhalers. Additionally, the unit dose kit can contain instructions for preparation and administration of the compositions. The kit may be, e.g., manufactured as a single use unit dose for one patient, multiple uses for a particular patient (e.g., at a constant dose or in which the individual compounds may vary in potency as therapy progresses), or the kit may contain multiple doses suitable for administration to multiple patients (e.g., bulk packaging). The kit components may be assembled in, e.g., cartons, blister packs, bottles, or tubes.
Dosages
Generally, when administered to a human, the dosage of any of the agents of the invention will depend on the nature of the agent, and can readily be determined by one skilled in the art. Typically, such dosage is normally about 0.001 mg to 2000 mg per day, desirably about 1 mg to 1000 mg per day, and more desirably about 5 mg to 500 mg per day.
Administration of each drug, alone or in combination, can be one to four times daily for one day to one year, and may even be for the life of the patient. Chronic, long-term administration will be required in many cases.
Appropriate dosages of compounds used in the methods described herein depend on several factors, including the administration method, the severity of the disorder, and the age, weight, and health of the patient to be treated. Additionally, pharmacogenomic information (e.g., the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile of a therapeutic) about a particular patient may affect the dosage used.
Additional Applications
If desired, the compounds of the invention may be employed in mechanistic assays to determine whether other single agents or combinations of agents are effective in the treatment or amelioration of a disorder associated with a defect in CFTR gene or protein using assays generally known in the art, examples of which are described herein. For example, candidate compounds may be tested, alone or in combination and contacted with cells that express a mutated CFTR (e.g., CTFR-ΔF508) and a fluorescent marker (e.g., yellow fluorescent protein (YFP)) to determine the functionality (e.g., openness) and/or abundance of the CFTR channels. After a suitable time, iodide is applied to the cells. By increasing the total number of channels or increasing the probability that the channels will be open, the CFTR therapeutic agents of the invention accelerate YFP quenching. Thus, an increase in the rate of fluorescence decay in this particular assay would indicate that the candidate compound would be a suitable CFTR therapeutic agent for the treatment of a disorder associated with a defect in CFTR gene or protein.
Examples
Example 1. CFTR YFP Ranking Screen and Identification of Therapeutic Agents for the Treatment of a Disorder Associated with a Defect in the CFTR Gene or Protein
The goal of the CFTR yellow fluorescent protein (YFP) ranking screen was to select single agents from a chemical library that increase recruitment of ΔF508 CFTR proteins to the plasma membrane of a cell or enhance existing CFTR channel activities. This screen was performed in Fischer rat thyroid (FRT) cell lines expressing both ΔF508 CFTR and YFP in a 384-well plate format. Four different assay protocols were used to identify these agents.
In one protocol, the cells were incubated with candidate compounds at 37°C for 24 hours. After washing, the cells were stimulated with forskolin and a compound known to open CFTR channels before being read on a plate reader. In the second assay, the number of ΔF508 CFTR channels in the plasma membrane was increased by incubating the cells at 27°C for 24 hours. The cells were then washed and treated with forskolin and the candidate compounds. In the third and fourth assays, the cells were incubated with candidate compounds at either 27°C or at 37°C for 24 hours, the plate-washing step was omitted, and the cells were stimulated with forskolin prior to reading on a plate reader. YFP fluorescence intensity was read with a plate reader at high speed before and after iodide was injected into each well of the plate. Iodide enters the cell via open CFTR channels in the plasma membrane and quenches YFP fluorescence. The rate of fluorescence decay is directly related to the total CFTR activity in the cell membranes. By increasing the total number of ΔF508 CFTR channels in the plasma membrane or their open probability, CFTR-ΔF508 therapeutic agents accelerate YFP quenching.
Materials and Methods The materials used in these assays included FRT cells stably expressing
ΔF508 CFTR and H148Q/I152L eYFP or H148Q/I152L eYFP only. The cells were cultured in T- 175 flasks (Corning, Catalog No. 431080) or CeIlF arm high-density flasks (Fisher, Catalog No. 13-700-407) with Coon's medium (Sigma, Catalog No. F6636) containing 10% FBS (Gibco, Catalog No. 26140), 1% Penicillin-Streptomycin (Cellgro, Catalog No. 30-002-CI), 2.68 g/L sodium bicarbonate, 2 mM L-glutamine (Gibco, Catalog No. 25030-081), and 1 mg/ml G418 for the YFP cells. One T- 175 flask of cells provided enough cells to seed two 384-well plates at 50,000 cells/well and 50 μl per well; one CellFarm flask seeded about ten times as much. Once the cells were confluent in the flasks, the cells were rinsed with
PBS (10 ml for a T- 175 flask; 50 ml for a CellFarm flask). Trypsin-EDTA was added to the cells (5 ml for a T- 175 flask; 50 ml for a CellFarm flask). The cells were incubated at 37°C for 10-15 minutes. Cell culture media was added to neutralize the trypsin and cells were vigorously pipetted to break apart cell clumps. For passaging, the cells were split at a ratio of 1 :3 or 1 :4 (30 ml media per T- 175 flask; 500 ml media per CellFarm flask). For seeding cells on assay plates, all cell suspensions were mixed together and the cell density was counted. Additional media was added to dilute the cells to a concentration of 1 million cells per ml. Cells were plated at 50,000 per well in 50 μl. PBS-iodide solution was made with the following concentrations of salts: 0.7 mM CaCl2, 2.7 mM KCl, 1.5 mM KH2PO4, 1.1 mM MgCl2, 154 mM NaI, and 8.1 mM NaHPO4, with the pH adjusted to 7.4.
With all assays, 50,000 cells in 50 μl media were plated in each well of a 384-well plate (Matrix). For the first assay, the plates were incubated for 60 minutes at 37°C and 5% CO2. The drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells. The plates were then incubated for 24 hours at 37°C and 5% CO2. The following day, the plates were washed twice with DPBS and stimulated with 20 μM forskolin and 3 μM CF-P3 in DPBS for 60 minutes at room temperature before making a fluorescence reading on a plate reader (Hamamatsu FDSS-6000). For the second assay, the plates were incubated for 24 hours at 27°C and
5% CO2. The following day, the plates were washed twice with DPBS and treated with drugs, diluted 1 : 100 in culture media and then added at a ratio of 1 :10 to the wells, and 20 μM forskolin for 60 minutes at room temperature before reading on the plate reader. For the third assay, the plates were incubated for 60 minutes at 27°C and
5% CO2. The drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells. The plates were then incubated for 24 hours at 27°C and 5% CO2. The following day, the plates were stimulated with 20 μM of forskolin added to the culture media and incubated for 60 minutes at room temperature before reading on the plate reader.
For the fourth assay, the plates were incubated for 60 minutes at 37°C and 5% CO2. The drugs were diluted 1 : 100 in culture media and then added at a ratio of 1 : 10 to the wells. The plates were then incubated for 24 hours at 37°C and 5% CO2. The following day, the plates were stimulated with 20 of μM forskolin for 60 minutes at room temperature before reading on the plate reader.
In the plate reader, the cells were excited with UV light at 500 nm and the fluorescence emitted at 540 nm was read at 5 Hz. After a 6-second baseline read, PBS-iodide was added to the wells.
Data Analysis
A representative sample of the data collected is shown in Figure 1. The amount of fluorescence remaining 10 seconds after adding iodide was recorded and the rate of fluorescence quenching was calculated using the following equation to fit the data: y = (Ao - A1)e-("<>* + Aϊ
The user input included t0 (injection time), tN (fluorescence level (FL) sample time), and tg (end of data fitting point). The return values included QR (fluorescence quenching rate, inverse of decay time constant tau) and FL (fluorescence level given in percentage number at t = tN). The endpoints included:
FL-delta = FLbackground - FL (default primary endpoint, used for Z' calculations) FL = 100 x Fluorescence (t = tN) I Fluorescence (t = to).
FLbackground = mean of FL of background wells (FLB)
The fluorescence level (FL) was normalized (0 to 100) at the sampling point (tu). Each FL value was taken from the kinetic fitting results to reduce noise and spikes from raw data. The quenching rate (QR) was determined by exponential fitting of the fluorescence decay from the point of iodide injection (to) to the end of fitting range (tE). QR has a dimension of s"1.
QRbackground = mean of QR of background wells (QRB)
A0 = initial fluorescence amplitude at t = t0 Ao was directly read from the raw data file generated by the plate reader used for QC.
The calculated values included:
FL- fold = (FLbackground " FL) / (FLbackground " FLuntreated)
FLuntreatec] was the mean value of FL from an untreated well. QR-fθld = QR / QRuntreated
QRumreated was the mean value of QR from an untreated well. Results
Table 4 shows enhancement of existing CFTR channel activities in cells contacted with the candidate compound compared to untreated cells (denoted as Max Fold).
Table 4
Figure imgf000070_0001
Figure imgf000071_0001
Compounds that increased the recruitment of ΔF508 CFTR proteins to the plasma membrane of cells are listed in Table 5. Table 5 shows compounds that increased recruitment of ΔF508 CFTR proteins to the plasma membrane in cells when contacted with the candidate compound compared to untreated cells (denoted as Max Fold).
Table 5
Figure imgf000071_0002
Figure imgf000072_0001
Table 6 shows the reference name and chemical name for each CF reference compound. Tables 7-21 show combinations of compounds that enhanced CFTR channel activities in cells contacted with the candidate compounds compared to untreated cells (denoted as Max Combination Effect (MCE, based on Max Fold) and Synergy Score (SS)). A synergy score was calculated by the formula S = logfx \ogfγ ∑ /data (/data-4oewe), summed over all non-single-agent concentration pairs, and where
Figure imgf000073_0001
are the natural logarithm of the dilution factors used for each single agent. This effectively calculates a volume between the measured and Loewe additive response surfaces, weighted towards high inhibition and corrected for varying dilution factors. In general, the magnitude of the synergy score indicates the strength of the synergistic interaction. To select desirable combinations for follow-up characterization, the following criteria were established: (1) significant synergy over the additive model as measured by the synergy score with a cut-off value = 2.0, and (2) substantial activity where the synergy occurs and/or sufficient potency shifting occurs, with a maximum effect (MCE) greater or equal to 2.0 for combinations.
Table 6. Reference Name and Chemical Name for Each CF Reference
Compound
Figure imgf000073_0002
Table 7. Corrector x Corrector Combinations with Maximum Combination Effect (MCE) and Synergy Scores (SS) > 2.0
Figure imgf000073_0003
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Table 8. HDAC Inhibitors x CF Correctors
Figure imgf000081_0002
Figure imgf000082_0001
Table 9. HDAC Inhibitors/CF Correctors x Statins
Figure imgf000082_0002
Figure imgf000083_0001
Figure imgf000084_0001
Table 11. CF Correctors x Steroids
Figure imgf000084_0002
Table 12. HDAC Inhibitors x Ion Channel Modulators Table 13. HDAC Inhibitors x Kinase Inhibitors
Figure imgf000085_0001
Figure imgf000086_0001
Table 15. HDAC Inhibitors x Receptor Modulators
Figure imgf000086_0002
Table 16. CF Correctors x PDE Inhibitors
Figure imgf000086_0003
Table 17. CF Correctors x Ion Channel Modulators
Figure imgf000087_0001
Table 18. CF Correctors x Kinase Inhibitors
Figure imgf000087_0002
Table 19. CF Correctors x Receptor Modulators
Figure imgf000087_0003
Table 20. Combinations without an HDAC Inhibitor or CF Modulator
Figure imgf000087_0004
Figure imgf000088_0001
Table 21. Best Corrector x Potentiator Combinations
Figure imgf000088_0002
Figure imgf000089_0001
Figure imgf000090_0001
Other Embodiments
All publications, patents, and patent applications mentioned in the above specification are hereby incorporated by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.
Other embodiments are in the claims. What is claimed is:

Claims

Claims
1. A composition comprising at least one agent selected from any one of the agents of Table 1, wherein said agent is present in an amount that, when administered to a patient, is sufficient to treat or ameliorate a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
2. The composition of claim 1, wherein said agent is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
3. The composition of claim 1, wherein said agent is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
4. A composition comprising:
(a) a first agent selected from Table 1 and
(b) a second, different agent selected from Table 1 , wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
5. The composition of claim 4, wherein one or both of said first and second agents is a statin, steroid, or flavonoid.
6. The composition of claim 5, wherein said statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
7. The composition of claim 5, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
8. The composition of claim 5, wherein said flavonoid is 2- hydroxyflavanone, licochalcone-A, chalcone, or fisetin.
9. A composition comprising:
(a) a first agent selected from Table 1 and
(b) a second agent selected from Table 2, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
10. The composition of claim 9, wherein said first or second agent is a statin, steroid, flavonoid, or dihydropyridine.
11. The composition of claim 10, wherein said statin is simvastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
12. The composition of claim 10, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, betamethasone, ethinyl estradiol, or fludrocortisone.
13. The composition of claim 10, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, quercetin, licochalcone-A, chalcone, fisetin, or 2- hydroxyflavanone.
14. The composition of claim 10, wherein said dihydropyridine is felodipine, isradipine, nimodipine, lercanidipine, or nisoldipine.
15. A composition comprising:
(a) a first agent selected from Table 1 and
(b) a second agent selected from Table 3, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
16. The composition of claim 15, wherein said first agent is a statin, steroid, or flavonoid.
17. The composition of claim 16, wherein said statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
18. The composition of claim 16, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
19. The composition of claim 16, wherein said flavonoid is 2- hydroxyflavanone, licochalcone-A, chalcone, or fisetin.
20. A composition comprising:
(a) a first agent selected from Table 2 and
(b) a second agent selected from Table 3, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
21. The composition of claim 20, wherein said first agent is a statin, steroid, flavonoid, or dihydropyridine.
22. The composition of claim 21, wherein said statin is simvastatin.
23. The composition of claim 21, wherein said steroid is betamethasone or ethinyl estradiol.
24. The composition of claim 21, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, or quercetin.
25. The composition of claim 21, wherein said dihydropyridine is lercanidipine, felodipine, isradipine, nimodipine, or nisoldipine.
26. A composition comprising:
(a) a first agent selected from Table 2 and
(b) a second, different agent selected from Table 2, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
27. The composition of claim 26, wherein one or both of said first and second agents is a statin, steroid, flavonoid, or dihydropyridine.
28. The composition of claim 27, wherein said statin is simvastatin.
29. The composition of claim 27, wherein said steroid is betamethasone or ethinyl estradiol.
30. The composition of claim 27, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, or quercetin.
31. The composition of claim 27, wherein said dihydropyridine is lercanidipine, felodipine, isradipine, nimodipine, or nisoldipine.
32. A composition comprising:
(a) a first agent selected from Table 1 ,
(b) a second agent selected from Table 2, and
(c) a third agent selected from Table 3, wherein said first, second, and third agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
33. The composition of claim 32, wherein said first or second agent is a statin, steroid, flavonoid, or dihydropyridine.
34. The composition of claim 33, wherein said statin is simvastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
35. The composition of claim 33, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, betamethasone, ethinyl estradiol, or fludrocortisone.
36. The composition of claim 33, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, quercetin, licochalcone-A, chalcone, fisetin, or 2- hy droxy flavanone .
37. The composition of claim 33, wherein said dihydropyridine is felodipine, isradipine, nimodipine, lercanidipine, or nisoldipine.
38. The composition of any one of claims 1-37, wherein said composition is formulated for oral administration.
39. The composition of any one of claims 1-37, wherein said composition is formulated for systemic administration.
40. The composition of any one of claims 1-37, wherein said composition is formulated for inhalation.
41. The composition of any one of claims 1-40, wherein said disorder is cystic fibrosis.
42. A method for treating or ameliorating a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein, said method comprising administering to a patient at least one agent selected from any one of the agents of Table 1 in an amount sufficient to treat or ameliorate said disorder.
43. The method of claim 42, wherein said agent is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
44. The method of claim 42, wherein said agent is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
45. A method for treating or ameliorating a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein, said method comprising administering to a patient:
(a) a first agent selected from Table 1 and
(b) a second, different agent selected from Table 1, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate said disorder.
46. The method of claim 45, wherein one or both of said first and second agents is a statin, steroid, or flavonoid.
47. The method of claim 46, wherein said statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
48. The method of claim 46, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
49. The method of claim 46, wherein said flavonoid is 2- hydroxyflavanone, licochalcone-A, chalcone, or fisetin.
50. A method for treating or ameliorating a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein, said method comprising administering to a patient:
(a) a first agent selected from Table 1 and
(b) a second agent selected from Table 2, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate said disorder.
51. The method of claim 50, wherein one or both of said first and second agents is a statin, steroid, flavonoid, or dihydropyridine.
52. The method of claim 51, wherein said statin is simvastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
53. The method of claim 51, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, betamethasone, ethinyl estradiol, or fludrocortisone.
54. The method of claim 51, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, quercetin, licochalcone-A, chalcone, fisetin, or 2- hydroxyflavanone.
55. The method of claim 51, wherein said dihydropyridine is felodipine, isradipine, nimodipine, lercanidipine, or nisoldipine.
56. A method for treating or ameliorating a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein, said method comprising administering to a patient:
(a) a first agent selected from Table 1 and
(b) a second agent selected from Table 3, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate said disorder.
57. The method of claim 56, wherein said first agent is a statin, steroid, or flavonoid.
58. The method of claim 57, wherein said statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
59. The method of claim 57, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
60. The method of claim 57, wherein said flavonoid is licochalcone-A, chalcone, fisetin, or 2-hydroxyflavanone.
61. A method for treating or ameliorating a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein, said method comprising administering to a patient:
(a) a first agent selected from Table 2 and
(b) a second agent selected from Table 3, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate said disorder.
62. The method of claim 61, wherein said first agent is a statin, steroid, fiavonoid, or dihydropyridine.
63. The method of claim 62, wherein said statin is simvastatin.
64. The method of claim 62, wherein said steroid is betamethasone or ethinyl estradiol.
65. The method of claim 62, wherein said fiavonoid is apigenin, genistein, isoliquiritigenin, or quercetin.
66. The method of claim 62, wherein said dihydropyridine is lercanidipine, felodipine, isradipine, nimodipine, or nisoldipine.
67. A method for treating or ameliorating a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein, said method comprising administering to a patient:
(a) a first agent selected from Table 2 and
(b) a second, different agent selected from Table 2, wherein said first and second agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate said disorder.
68. The method of claim 67, wherein said first agent is a statin, steroid, fiavonoid, or dihydropyridine.
69. The method of claim 68, wherein said statin is simvastatin.
70. The method of claim 68, wherein said steroid is betamethasone or ethinyl estradiol.
71. The method of claim 68, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, or quercetin.
72. The method of claim 68, wherein said dihydropyridine is lercanidipine, felodipine, isradipine, nimodipine, or nisoldipine.
73. A method for treating or ameliorating a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein, said method comprising administering to a patient:
(a) a first agent selected from Table 1,
(d) a second agent selected from Table 2, and
(e) a third agent selected from Table 3, wherein said first, second, and third agents are present in amounts that, when administered to a patient, are sufficient to treat or ameliorate said disorder.
74. The method of claim 73, wherein one or both of said first and second agents is a statin, steroid, flavonoid, or dihydropyridine.
75. The method of claim 74, wherein said statin is simvastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
76. The method of claim 74, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, betamethasone, ethinyl estradiol, or fludrocortisone.
77. The method of claim 74, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, quercetin, licochalcone-A, chalcone, fisetin, or 2- hydroxyflavanone.
78. The method of claim 74, wherein said dihydropyridine is felodipine, isradipine, nimodipine, lercanidipine, or nisoldipine.
79. The method of any one of claims 45-72, wherein said first and second agents are administered simultaneously.
80. The method of any one of claims 45-72, wherein said first and second agents are administered within 24 hours of each other.
81. The method of any one of claims 45-72, wherein said first and second agents are administered within 7 days of each other.
82. The method of any one of claims 45-72, wherein said first and second agents are administered within 14 days of each other.
83. The method of any one of claims 45-72, wherein said first and second agents are administered within 28 days of each other.
84. The method of any one of claims 73-78, wherein said first, second, and third agents are administered simultaneously.
85. The method of any one of claims 73-78, wherein said first, second, and third agents are administered within 24 hours of each other.
86. The method of any one of claims 73-78, wherein said first, second, and third agents are administered within 7 days of each other.
87. The method of any one of claims 73-78, wherein said first, second, and third agents are administered within 14 days of each other.
88. The method of any one of claims 73-78, wherein said first, second, and third agents are administered within 28 days of each other.
89. The method of any one of claims 42-88, wherein said agent(s) are formulated for oral administration.
90. The method of any one of claims 42-88, wherein said agent(s) are formulated for systemic administration.
91. The method of any one of claims 42-88, wherein said agent(s) are formulated for inhalation.
92. The method of any one of claims 42-91, wherein said disorder is cystic fibrosis.
93. A kit comprising:
(a) at least one agent selected from any one of the agents of Table 1 and
(b) instructions for administering said agent to a patient having a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
94. The kit of claim 93, wherein said agent is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
95. The kit of claim 93, wherein said agent is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
96. A kit comprising:
(a) a first agent selected from Table 1 ,
(b) a second, different agent selected from Table 1 , and
(c) instructions for administering said first and second agents to a patient having a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
97. The kit of claim 96, wherein one or both of said first and second agents is a statin, steroid, or flavonoid.
98. The kit of claim 97, wherein said statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
99. The kit of claim 97, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
100. The kit of claim 97, wherein said flavonoid is licochalcone-A, chalcone, fisetin, or 2-hydroxyflavanone.
101. A kit comprising:
(a) a first agent selected from Table 1 ,
(b) a second agent selected from Table 2, and
(c) instructions for administering said first and second agents to a patient having a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
102. The kit of claim 101, wherein one or both of said first and second agents is a statin, steroid, flavonoid, or dihydropyridine.
103. The kit of claim 102, wherein said statin is simvastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
104. The kit of claim 102, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, betamethasone, ethinyl estradiol, or fludrocortisone.
105. The kit of claim 102, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, quercetin, licochalcone-A, chalcone, fisetin, or 2- hydroxyflavanone.
106. The kit of claim 102, wherein said dihydropyridine is felodipine, isradipine, nimodipine, lercanidipine, or nisoldipine.
107. A kit comprising:
(a) a first agent selected from Table 1 and
(b) a second agent selected from Table 3,
(c) instructions for administering said first and second agents to a patient having a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
108. The kit of claim 107, wherein said first agent is a statin, steroid, or flavonoid.
109. The kit of claim 108, wherein said statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
110. The kit of claim 108, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, or fludrocortisone.
11 1. The kit of claim 108, wherein said flavonoid is licochalcone-A, chalcone, fisetin, or 2-hydroxyflavanone.
112. A kit comprising:
(a) a first agent selected from Table 2,
(b) a second agent selected from Table 3, and
(c) instructions for administering said first and second agents to a patient having a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
1 13. The kit of claim 112, wherein said first agent is a statin, steroid, flavonoid, or dihydropyridine.
114. The kit of claim 1 13, wherein said statin is simvastatin.
115. The kit of claim 113, wherein said steroid is betamethasone or ethinyl estradiol.
1 16. The kit of claim 1 13, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, or quercetin.
117. The kit of claim 113, wherein said dihydropyridine is lercanidipine, felodipine, isradipine, nimodipine, or nisoldipine.
118. A kit comprising:
(a) a first agent selected from Table 2,
(b) a second, different agent selected from Table 2, and
(c) instructions for administering said first and second agents to a patient having a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
119. The kit of claim 118, wherein said first agent is a statin, steroid, flavonoid, or dihydropyridine.
120. The kit of claim 119, wherein said statin is simvastatin.
121. The kit of claim 119, wherein said steroid is betamethasone or ethinyl estradiol.
122. The kit of claim 119, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, or quercetin.
123. The kit of claim 119, wherein said dihydropyridine is lercanidipine, felodipine, isradipine, nimodipine, or nisoldipine.
124. A kit comprising:
(a) a first agent selected from Table 1 ,
(b) a second agent selected from Table 2, and
(c) a third agent selected from Table 3,
(d) instructions for administering said first and second agents to a patient having a disorder associated with a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or protein.
125. The kit of claim 124, wherein one or both of said first and second agents is a statin, steroid, flavonoid, or dihydropyridine.
126. The kit of claim 125, wherein said statin is simvastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin, or rosuvastatin.
127. The kit of claim 125, wherein said steroid is corticosterone, fluocinonide, fluprednisolone, rimexolone, triamcinolone, beclomethasone, betamethasone, ethinyl estradiol, or fludrocortisone.
128. The kit of claim 125, wherein said flavonoid is apigenin, genistein, isoliquiritigenin, quercetin, licochalcone-A, chalcone, fisetin, or 2- hydroxyflavanone.
129. The kit of claim 125, wherein said dihydropyridine is felodipine, isradipine, nimodipine, lercanidipine, or nisoldipine.
130. The kit of any one of claims 93-129, wherein said disorder is cystic fibrosis.
PCT/US2009/001061 2008-02-19 2009-02-19 Methods and compositions for the treatment of disorders associated with defects of the cystic fibrosis transmembrane conductance regulator gene or protein WO2009105234A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US6625908P 2008-02-19 2008-02-19
US61/066,259 2008-02-19

Publications (2)

Publication Number Publication Date
WO2009105234A2 true WO2009105234A2 (en) 2009-08-27
WO2009105234A3 WO2009105234A3 (en) 2009-11-12

Family

ID=40986104

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/001061 WO2009105234A2 (en) 2008-02-19 2009-02-19 Methods and compositions for the treatment of disorders associated with defects of the cystic fibrosis transmembrane conductance regulator gene or protein

Country Status (1)

Country Link
WO (1) WO2009105234A2 (en)

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITRM20110231A1 (en) * 2011-05-09 2012-11-10 Gb Pharma S R L USE OF TAMOXIFENE IN THERAPY OF CYSTIC FIBROSIS.
EP2664326A1 (en) * 2012-05-17 2013-11-20 I.E.R.F.C. European Institute for Cystic Fibrosis Research Combined therapy for cystic fibrosis
WO2014015672A1 (en) * 2012-07-24 2014-01-30 兆科药业（广州）有限公司 Compound preparation of lercanidipine and atorvastatin
WO2014026959A1 (en) * 2012-08-13 2014-02-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for treatment of cystic fibrosis
WO2014086687A1 (en) 2012-12-03 2014-06-12 Universita' Degli Studi Di Padova A cftr corrector for the teatment of genetic disorders affecting striated muscle
WO2015116735A1 (en) * 2014-01-28 2015-08-06 Mayo Foundation For Medical Education And Research Methods and combinations for killing senescent cells and for treating senescence-associated diseases and disorders
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US9233103B2 (en) 2011-03-25 2016-01-12 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating heartburn, gastric bleeding or hemorrhage in patients receiving clopidogrel therapy
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US20160220511A1 (en) * 2009-09-14 2016-08-04 Nestec S.A. Nutritional compositions for modulating inflammation including exogenous vitamin k2
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
ITUA20162292A1 (en) * 2016-04-05 2017-10-05 Gb Pharma S R L Use of tamoxifen for the treatment of cystic fibrosis in patients of both sexes
US9849128B2 (en) 2014-01-28 2017-12-26 Unity Biotechnology, Inc. Unit dose of a cis-imidazoline for treating an osteoarthritic joint by removing senescent cells
US9884065B2 (en) 2011-12-13 2018-02-06 Buck Institute For Research On Aging Inhibiting activity of senescent cells using a glucocorticoid
US9901080B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse having a transgene that converts a prodrug into a cytotoxic compound in senescent cells
US9901081B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse for determining the role of senescent cells in cancer
US9968076B2 (en) 2011-06-21 2018-05-15 Mayo Foundation For Medical Education And Research Transgenic animals capable of being induced to delete senescent cells
WO2018141678A1 (en) * 2017-01-31 2018-08-09 Medizinische Hochschule Hannover (Mhh) Natural compounds and fibrosis
US10279018B2 (en) 2012-12-03 2019-05-07 Unity Biotechnology, Inc. Immunogenic compositions for inducing an immune response for elimination of senescent cells
US10328058B2 (en) 2014-01-28 2019-06-25 Mayo Foundation For Medical Education And Research Treating atherosclerosis by removing senescent foam cell macrophages from atherosclerotic plaques
US10378002B2 (en) 2012-04-17 2019-08-13 Unity Biotechnology, Inc. Replication conditional virus that specifically kills senescent cells
US10456344B2 (en) 2014-12-22 2019-10-29 Conopco, Inc. Hair composition
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
JP2020193188A (en) * 2019-05-30 2020-12-03 国立大学法人福井大学 Agent for preventing or treating chronic sinusitis, and use of statin for producing the same
WO2021130381A1 (en) * 2019-12-26 2021-07-01 Centre D'etude Des Cellules Souches (Cecs) Combination of a hdac inhibitor and vx molecules, and its use for the treatment of cystic fibrosis
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
CN115177615A (en) * 2022-08-04 2022-10-14 湖南中医药大学 Application of psoralen in estrogen-promoting medicine
CN116196308A (en) * 2023-03-13 2023-06-02 华中科技大学同济医学院附属同济医院 Application of albendazole in preparing medicament for preventing and/or treating individual fibrosis diseases

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20010006656A1 (en) * 1999-02-17 2001-07-05 University Of Washington Methods and compositions for inhibiting inflammation associated with pulmonary disease
US20030096762A1 (en) * 1997-10-16 2003-05-22 Children's Hospital Oakland Compositions and methods for cystic fibrosis therapy
US20050158747A1 (en) * 2003-05-30 2005-07-21 Whitsett Jeffrey A. CFTR modifier genes and expressed polypeptides useful in treating cystic fibrosis and methods and products for detecting and/or identifying same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030096762A1 (en) * 1997-10-16 2003-05-22 Children's Hospital Oakland Compositions and methods for cystic fibrosis therapy
US20010006656A1 (en) * 1999-02-17 2001-07-05 University Of Washington Methods and compositions for inhibiting inflammation associated with pulmonary disease
US20050158747A1 (en) * 2003-05-30 2005-07-21 Whitsett Jeffrey A. CFTR modifier genes and expressed polypeptides useful in treating cystic fibrosis and methods and products for detecting and/or identifying same

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
BRICE MARCET ET AL.: 'General anesthetic octanol and related compounds activate wild-type and delF508 cystic fibrosis chloride channels.' BRITISH JOURNAL OF PHARMACOLOGY. vol. 141, no. 6, 2004, ISSN 0007-1188 pages 905 - 914 *
HENRY A. WOJTCZAK ET AL.: 'Beclomethasone diproprionate reduced airway inflammation without adrenal suppression in young children with cystic fibrosis: A pilot study.' PEDIATRIC PULMONOLOGY. vol. 32, no. 4, 2001, ISSN 8755-6863 pages 293 - 302 *
KREISELMEIER N.E. ET AL.: 'Statin-mediated correction of STAT1 signaling and inducible nitric oxide synthase expression in cystic fibrosis epithelial cells.' AMERICAN JOURNAL OF PHYSIOLOGY. LUNG CELLULAR AND MOLECULAR PHYSIOLOGY vol. 285, no. 6, 2003, ISSN 1040-0605 pages L1286 - L1295 *
PEDEMONTE N. ET AL.: 'Antihypertensive 1,4-dihydropyridines as Correctors of the Cystic Fibrosis transmembrance Conductance Regulator Channel Gating Defect caused by Cystic Fibrosis Mutations.' MOLECULAR PHARMACOLOGY vol. 68, no. 6, 2005, ISSN 0026-895X pages 1736 - 1746 *
SCHMIDT A. ET AL.: 'Prolonged treatment of cells with genistein modulates the expression and function of the cystic fibrosis transmembane conductance regulator.' BRITISH JOURNAL OF PHARMACOLOGY. vol. 153, no. 6, 28 January 2008, ISSN 0007-1188 pages 1311 - 1323 *

Cited By (67)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10596162B2 (en) 2005-02-03 2020-03-24 Wyeth Llc Method for treating gefitinib resistant cancer
US10603314B2 (en) 2005-02-03 2020-03-31 The General Hospital Corporation Method for treating gefitinib resistant cancer
US10729672B2 (en) 2005-11-04 2020-08-04 Wyeth Llc Antineoplastic combinations with mTOR inhibitor, trastuzumab and/or HKI-272
US9630946B2 (en) 2007-10-17 2017-04-25 Wyeth Llc Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US9139558B2 (en) 2007-10-17 2015-09-22 Wyeth Llc Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10035788B2 (en) 2007-10-17 2018-07-31 Wyeth Llc Maleate salts of (E)-N-{4[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof
US10111868B2 (en) 2008-06-17 2018-10-30 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9511063B2 (en) 2008-06-17 2016-12-06 Wyeth Llc Antineoplastic combinations containing HKI-272 and vinorelbine
US9265784B2 (en) 2008-08-04 2016-02-23 Wyeth Llc Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine
US9211291B2 (en) 2009-04-06 2015-12-15 Wyeth Llc Treatment regimen utilizing neratinib for breast cancer
US20160220511A1 (en) * 2009-09-14 2016-08-04 Nestec S.A. Nutritional compositions for modulating inflammation including exogenous vitamin k2
US9687456B2 (en) * 2009-09-14 2017-06-27 Nestec S.A. Nutritional compositions for modulating inflammation including exogenous vitamin K2
US9233103B2 (en) 2011-03-25 2016-01-12 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating heartburn, gastric bleeding or hemorrhage in patients receiving clopidogrel therapy
US9889125B2 (en) 2011-03-25 2018-02-13 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating heartburn, gastric bleeding or hemorrhage in patients receiving clopidogrel therapy
ITRM20110231A1 (en) * 2011-05-09 2012-11-10 Gb Pharma S R L USE OF TAMOXIFENE IN THERAPY OF CYSTIC FIBROSIS.
US9968076B2 (en) 2011-06-21 2018-05-15 Mayo Foundation For Medical Education And Research Transgenic animals capable of being induced to delete senescent cells
US10251376B2 (en) 2011-06-21 2019-04-09 Mayo Foundation For Medical Education And Research Increasing healthy lifespan and delaying progression of age-related phenotypes by selectively removing senescent cells
US9884065B2 (en) 2011-12-13 2018-02-06 Buck Institute For Research On Aging Inhibiting activity of senescent cells using a glucocorticoid
US10378002B2 (en) 2012-04-17 2019-08-13 Unity Biotechnology, Inc. Replication conditional virus that specifically kills senescent cells
US9132123B2 (en) 2012-05-17 2015-09-15 I.E.R.F.C. European Institute For Cystic Fibrosis Research Combined therapy for cystic fibrosis
US9730922B2 (en) 2012-05-17 2017-08-15 I.E.R.F.C. Europ. Inst. for Cystic. Fibrosis Res. Combined therapy for cystic fibrosis
EP2664326A1 (en) * 2012-05-17 2013-11-20 I.E.R.F.C. European Institute for Cystic Fibrosis Research Combined therapy for cystic fibrosis
WO2014015672A1 (en) * 2012-07-24 2014-01-30 兆科药业（广州）有限公司 Compound preparation of lercanidipine and atorvastatin
US9402821B2 (en) 2012-08-13 2016-08-02 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for treatment of cystic fibrosis
WO2014026959A1 (en) * 2012-08-13 2014-02-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for treatment of cystic fibrosis
US10655144B2 (en) 2012-08-23 2020-05-19 Buck Institute For Research On Aging Nucleic acid construct with a p16 promoter that causes a prodrug converting enzyme to be expressed specifically in senescent cells
US9901081B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse for determining the role of senescent cells in cancer
US9901080B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse having a transgene that converts a prodrug into a cytotoxic compound in senescent cells
US10279018B2 (en) 2012-12-03 2019-05-07 Unity Biotechnology, Inc. Immunogenic compositions for inducing an immune response for elimination of senescent cells
WO2014086687A1 (en) 2012-12-03 2014-06-12 Universita' Degli Studi Di Padova A cftr corrector for the teatment of genetic disorders affecting striated muscle
US10478433B2 (en) 2014-01-28 2019-11-19 Unity Biotechnology, Inc. Unit dose of an aryl sulfonamide that is effective for treating eye disease and averting potential vision loss
US10010546B2 (en) 2014-01-28 2018-07-03 Unity Biotechnology, Inc. Treatment of ophthalmic conditions by selectively removing senescent cells from the eye
US11980616B2 (en) 2014-01-28 2024-05-14 Mayo Foundation For Medical Education And Research Treating liver disease by selectively eliminating senescent cells
US9993472B2 (en) 2014-01-28 2018-06-12 Unity Biotechnology, Inc. Treatment for osteoarthritis in a joint by administering a means for inhibiting MDM2
US10130628B2 (en) 2014-01-28 2018-11-20 Unity Biotechnology, Inc. Treatment of joint pain
US10213426B2 (en) 2014-01-28 2019-02-26 Unity Biotechnology, Inc. Method of optimizing conditions for selectively removing a plurality of senescent cells from a tissue or a mixed cell population
US9980962B2 (en) 2014-01-28 2018-05-29 Unity Biotechnology, Inc Use of sulfonamide inhibitors of Bcl-2 to treat senescence-associated lung conditions such as pulmonary fibrosis and chronic obstructive pulmonary disease
US10258618B2 (en) 2014-01-28 2019-04-16 Unity Biotechnology, Inc. Treating pulmonary conditions by selectively removing senescent cells from the lung using an intermittent dosing regimen
US11351167B2 (en) 2014-01-28 2022-06-07 Buck Institute For Research On Aging Treating cognitive decline and other neurodegenerative conditions by selectively removing senescent cells from neurological tissue
US9855266B2 (en) 2014-01-28 2018-01-02 Unity Biotechnology, Inc. Treatment for osteoarthritis by intra-articular administration of a cis-imidazoline
US10328073B2 (en) 2014-01-28 2019-06-25 Unity Biotechnology, Inc. Use of sulfonamide inhibitors of BCL-2 and BCL-xL to treat ophthalmic disease by selectively removing senescent cells
US10328058B2 (en) 2014-01-28 2019-06-25 Mayo Foundation For Medical Education And Research Treating atherosclerosis by removing senescent foam cell macrophages from atherosclerotic plaques
US9849128B2 (en) 2014-01-28 2017-12-26 Unity Biotechnology, Inc. Unit dose of a cis-imidazoline for treating an osteoarthritic joint by removing senescent cells
US11517572B2 (en) 2014-01-28 2022-12-06 Mayo Foundation For Medical Education And Research Killing senescent cells and treating senescence-associated conditions using a SRC inhibitor and a flavonoid
US10413542B2 (en) 2014-01-28 2019-09-17 Buck Institute For Research On Aging Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders using an inhibitor of Akt kinase
WO2015116735A1 (en) * 2014-01-28 2015-08-06 Mayo Foundation For Medical Education And Research Methods and combinations for killing senescent cells and for treating senescence-associated diseases and disorders
US10478432B2 (en) 2014-01-28 2019-11-19 Unity Biotechnology, Inc. Compositions of matter for treatment of ophthalmic conditions by selectively removing senescent cells from the eye
US11963957B2 (en) 2014-01-28 2024-04-23 Mayo Foundation For Medical Education And Research Treating cardiovascular disease by selectively eliminating senescent cells
US10517866B2 (en) 2014-01-28 2019-12-31 Unity Biotechnology, Inc. Removing senescent cells from a mixed cell population or tissue using a phosphoinositide 3-kinase (PI3K) inhibitor
US10456344B2 (en) 2014-12-22 2019-10-29 Conopco, Inc. Hair composition
US10941175B2 (en) 2015-08-06 2021-03-09 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9708359B2 (en) 2015-08-06 2017-07-18 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US9701706B2 (en) 2015-08-06 2017-07-11 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US10407457B2 (en) 2015-08-06 2019-09-10 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
US11981700B2 (en) 2015-08-06 2024-05-14 Chimerix, Inc. Pyrrolopyrimidine nucleosides and analogs thereof
ITUA20162292A1 (en) * 2016-04-05 2017-10-05 Gb Pharma S R L Use of tamoxifen for the treatment of cystic fibrosis in patients of both sexes
US11191738B2 (en) 2016-04-05 2021-12-07 Gb Pharma S.R.L. Use of tamoxifen for the treatment of cystic fibrosis in patients of both sexes
EA036682B1 (en) * 2016-04-05 2020-12-08 Гб Фарма С.Р.Л. Use of tamoxifen for the treatment of cystic fibrosis in patients of both sexes
WO2017174529A1 (en) * 2016-04-05 2017-10-12 Gb Pharma S.R.L. Use of tamoxifen for the treatment of cystic fibrosis in patients of both sexes
JP2019510791A (en) * 2016-04-05 2019-04-18 ジビ ファルマ エッセ．エッレ．エッレ Use of tamoxifen for the treatment of cystic fibrosis in patients of both sexes
US11185539B2 (en) 2017-01-31 2021-11-30 Medizinische Hochschule Hannover (Mhh) Natural compounds and fibrosis
WO2018141678A1 (en) * 2017-01-31 2018-08-09 Medizinische Hochschule Hannover (Mhh) Natural compounds and fibrosis
US11111264B2 (en) 2017-09-21 2021-09-07 Chimerix, Inc. Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide and uses thereof
JP2020193188A (en) * 2019-05-30 2020-12-03 国立大学法人福井大学 Agent for preventing or treating chronic sinusitis, and use of statin for producing the same
WO2021130381A1 (en) * 2019-12-26 2021-07-01 Centre D'etude Des Cellules Souches (Cecs) Combination of a hdac inhibitor and vx molecules, and its use for the treatment of cystic fibrosis
CN115177615A (en) * 2022-08-04 2022-10-14 湖南中医药大学 Application of psoralen in estrogen-promoting medicine
CN116196308A (en) * 2023-03-13 2023-06-02 华中科技大学同济医学院附属同济医院 Application of albendazole in preparing medicament for preventing and/or treating individual fibrosis diseases

Also Published As

Publication number Publication date
WO2009105234A3 (en) 2009-11-12

Similar Documents

Publication Publication Date Title
WO2009105234A2 (en) Methods and compositions for the treatment of disorders associated with defects of the cystic fibrosis transmembrane conductance regulator gene or protein
US6232315B1 (en) Method for treating inflammatory diseases by administering a thrombin inhibitor
US20080161324A1 (en) Compositions and methods for treatment of viral diseases
US10632116B2 (en) Combinations of serotonin receptor agonists for treatment of movement disorders
KR102347721B1 (en) PPAR compounds for use in the treatment of fibrotic diseases
CN104994854A (en) Methods of treating autoimmune, respiratory and inflammatory disorders by inhalation of roflumilast N-oxide
US20110306601A1 (en) Pharmacological modulation of positive ampa receptor modulator effects on neurotrophin expression
AU2018392985A1 (en) Compositions and methods of treatment for neurological disorders comprising motor neuron diseases
US20230158103A1 (en) Pld for use in combination in the treatment of coronavirus
EP1872795A1 (en) Therapeutic agent for irritable bowel syndrome
US20060281722A1 (en) Compounds and uses thereof
JP2020510045A (en) Pharmaceutical combinations containing ponesimod
US20140221385A1 (en) Combinations of serotonin receptor agonists for treatment of movement disorders
CN110087653A (en) For treating the combination treatment of pulmonary hypertension
RU2322238C2 (en) Treatment of proliferative arthritis
US20080200489A1 (en) Combination of Organic Compounds
CN113271949B (en) Sildenafil for the treatment of osteoarthritis
US20220040162A1 (en) Compositions comprising a crac inhibitor and a corticosteroid and methods of use thereof
US20150164916A1 (en) Roflumilast compositions for the treatment of copd
EP3936132A1 (en) Azelastine as antiviral treatment
JP2024512816A (en) How to treat inflammation
AU2023244808A1 (en) Therapeutic agent for respiratory disease
JP2003528050A (en) Use of pyrimidine-based endothelin antagonists in pets
NZ766879A (en) Method of treatment and compositions comprising a dual pi3k delta-gamma kinase inhibitor and a corticosteroid
NZ729419A (en) Method of treatment and compositions comprising a dual pi3k delta-gamma kinase inhibitor and a corticosteroid

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09712036

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09712036

Country of ref document: EP

Kind code of ref document: A2