WO2004052390A1 - Methodes et compositions de traitement du syndrome stein-leventhal - Google Patents

Methodes et compositions de traitement du syndrome stein-leventhal Download PDF

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WO2004052390A1
WO2004052390A1 PCT/US2003/023715 US0323715W WO2004052390A1 WO 2004052390 A1 WO2004052390 A1 WO 2004052390A1 US 0323715 W US0323715 W US 0323715W WO 2004052390 A1 WO2004052390 A1 WO 2004052390A1
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xaa
exendin
ala
analogs
group
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PCT/US2003/023715
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WO2004052390B1 (fr
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Nigel R. A. Beeley
Kathyrn Prickett
Andrew Young
David R. Hathaway
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Amylin Pharmaceuticals, Inc.
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Priority claimed from US10/317,126 external-priority patent/US7105489B2/en
Application filed by Amylin Pharmaceuticals, Inc. filed Critical Amylin Pharmaceuticals, Inc.
Priority to JP2005508433A priority Critical patent/JP2006520747A/ja
Priority to AU2003256988A priority patent/AU2003256988A1/en
Priority to EP03812761A priority patent/EP1581247A4/fr
Publication of WO2004052390A1 publication Critical patent/WO2004052390A1/fr
Publication of WO2004052390B1 publication Critical patent/WO2004052390B1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to endocrinology and pharmacology. More particularly, it relates to methods and compositions for treating subjects suffering from polycystic ovary syndrome (PCOS).
  • PCOS polycystic ovary syndrome
  • PCOS Polycystic ovary syndrome
  • Stein-Leventhal syndrome affects an estimated 6-10% of women in the United States.
  • PCOS is characterized by anovulation (irregular or absent menstrual periods) and hyperandrogenism (elevated serum testosterone and androstenedione). Additional etiological and clinical symptoms of this disease can include abnormal uterine bleeding, enlarged multifollicular ovaries, infertility, obesity, insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, type-2 diabetes mellitus, excess facial hair growth, hair loss and acne.
  • Insulin resistance and hyperinsulinemia are highly prevalent in patients with PCOS and are thought to underlie the pathophysiology of this disease (Udoff, L., et al., Curr. Opin. Obstret. Gynecol. 7:340-343 (1995); Barbieri, R.L., Am. J. Obstet. Gynecol. 183:1412-8 (2000); Kim, L.H. et al., Fertility and Sterility 73:1097-1098 (2000); Iuorno, M . et al, Obstet. Gynecol. Clin. North Am. 28:153-164 (2001); Zacur, H.Z., Obs-tet. Gynecol. Clin. North Am.
  • hyperandrogenism suppresses follicle stimulating hormone (FSH) secretion, alters gonadotropin-releasing hormone (GnRH) release and increases lutenizing hormone (LH) secretion.
  • FSH follicle stimulating hormone
  • GnRH gonadotropin-releasing hormone
  • LH lutenizing hormone
  • PCOS hirsutism and menstrual irregularities were treated with anti- androgenic drugs, including birth control pills, spironolactone, flutamide or finasteride.
  • Infertility treatments have included weight loss diets, ovulation medications (e.g., clomiphene, follistim and Gonal-F), so-called "ovarian drilling" surgery, and in vitro fertilization. More recent treatments for PCOS are targeted towards lowering insulin levels.
  • Insulin-sensitizing agents such as metformin, D-Chiro-inositol, diazoxide, and PPAR-gamma inhibitors (e.g., troglitazone (Rezulin), rosiglitazone (Avandia) and pioglitazone (Actos)), have been demonstrated to restore fertility and reverse the endocrine abnormalities associated with PCOS.
  • metformin and PPAR-gamma inhibitors do not interfere with pregnancy, they are generally discontinued during pregnancy because of concern over their safety and effect(s) on the fetus.
  • women with PCOS who become pregnant experience spontaneous abortion during the first trimester at rates as high as 3 0% to 50% (Iuorno, MJ.
  • GLP-1 GLP-1
  • exendin agonists and analogs of these compounds are capable of lowering insulin resistance or increasing insulin sensitivity.
  • the present invention relates to methods for treating PCOS using GLP-1, GLP-1 agonists, exendin, or exendin agonists.
  • the methods of this invention comprise administering to a patient a therapeutically effective amount of GLP-1, GLP-1 agonists, exendin, or exendin agonists.
  • the method comprises reducing or preventing insulin resistance in a subject suffering from PCOS.
  • the method comprises preventing the onset of type-2 diabetes in a subject suffering from PCOS.
  • the 5 method comprises restoring regular menses, ovulation, or fertility in a subject suffering from PCOS.
  • the GLP-1 agonist is a GLP-1 analog with agonist activity
  • the exendin agonist is an exendin analog with agonist activity.
  • the subject is human.
  • GLP-1 agonist is meant a compound that mimics the effects of GLP- 1 on PCOS by binding to the receptor or receptors where GLP- 1 causes this effect.
  • GLP-1 analogs with agonist activity are described in Chen et al., U.S. Patent No. 5,512,549, issued April 30, 1996, entitled Glucagon-Like Insulinotropic Peptide Analogs, Compositions and Methods of Use.
  • Other GLP- 1 analogs with agonist activity are described in Johnson et al.,
  • exendin agonist a compound that mimics the effects of exendin on
  • exendin analogs having agonist activity are described in U.S. Provisional Patent Application Serial No. 60/055,404, filed August 8, 1997, which enjoys common ownership with the present invention and is hereby incorporated by this reference.
  • Certain other exendin analogs 5 with agonist activity are described in U.S. Provisional Patent 2 5 Application Serial Nos. 60/066,029 and 60/065,442, both filed November 14, 1997 which enjoy common ownership with the present invention and are hereby incorporated by this reference.
  • Preferred exendin analogs having agonist activity include those described in U.S. Provisional Patent Application Serial Nos. 60/055,404 and 60/065,442. Detailed Description of the Invention
  • alopecia refers to a condition in which a patient experiences loss of hair due to, e.g., infections of the scalp or skin, nervousness, or a specific 5 disease such as PCOS.
  • the hair may fall out in patches or there may be diffuse loss of hair instead of complete baldness in one area.
  • exendin refers to naturally occurring exendin peptides that are found in the salivary secretions of the Gila-monster.
  • Preferred exendins include exendin-3 [SEQ. ID. NO. 7], which is present in the salivary secretions of Heloderma harridum, and exendin-4 ,0 [SEQ. ID. NO. 9], which is a peptide present in the salivary secretions of Heloderma suspectum (Eng, J., et al, J. Biol. Chem., 265:20259-62, 1990; Eng., J., et al, J. Biol. Chem., 267:7402-05, 1992).
  • Exendin-4 as it occurs in the salivary secretions of the Gila monster, is an amidated peptide.
  • exendin As it occurs in the salivary secretions of the Gila monster, is an amidated peptide.
  • exendin refers to both the amidated form of the peptide and the acid form of the -5 peptide.
  • Exendin-4 was first thought to be a (potentially toxic) component of the venom. It now appears that exendin-4 is devoid of toxicity, and that it instead is made in salivary glands in the Gila monster. The exendins have some sequence similarity to several members of the glucagon-like peptide family, with the highest homology, 53%, being to GLP-1 [7-36]NH2 50 (Goke, et al, J. Biol. Chem., 268:19650-55, 1993). "Exendin agonist” refers to compounds that mimic the effect of an exendin by binding to the receptor or receptors where the exendin causes this effect.
  • E xendin "agonist activity" in this context means having the biological activity of an exendin, but it is understood that the activity of the analog can be either less potent or more potent than the native exendin.
  • exendin agonists include, e.g., chemical compounds specifically designed to active that receptor or receptors at which an exendm 5 exerts its affect on PCOS.
  • GLP-1 and "glucagon-like peptide- 1,” according to this invention both refer to GLP-1 amide [SEQ. ID. NO. 4], as well as the acid form of GLP-1, which is also known as proglucagon[78-107].
  • GLP-1 agonist refers to compounds that mimic the effects of GLP-1 on PCOS by binding to the receptor or receptors where GLP-1 causes this effect. 0 Preferred GLP-1 agonists are GLP-1 analogs with agonist activity.
  • GLP-1 "agonist activity” in this context means having the biological activity of GLP-1 (7-36) amide (GLP-1(7- 36)NH 2 ), but it is understood that the activity of the analog can be either less potent or more potent than native GLP-l(7-36) amide.
  • GLP-1 agonists include, e.g., chemical compounds specifically designed to activate the receptor or receptors at which GLP-1 exerts 5 its affect on PCOS.
  • hirsutism refers to a condition in which a patient exhibits abnormal hairiness.
  • hypoandrogenism refers to a condition in which a patient exhibits elevated levels of androgens (e.g., testosterone, androstenedione) in serum.
  • hypoinsulinemia refers to a condition in which a patient exhibits elevated plasma insulin levels.
  • the t erm " hyperlipidemia" a s u sed h erein, r efers t o a condition i n w hich a patient exhibits elevated concentrations of any or all lipids in plasma.
  • hypertension refers to a condition in which a patient '.5 experiences persistently high blood pressure (i.e., a systolic pressure equal or greater than 140 mm Hg and a diastolic pressure equal to or greater than 90 mm Hg).
  • insulinotropic refers to an ability to stimulate the release of insulin into the circulation.
  • insulin resistance describes a subnormal biological 50 response to a given concentration of insulin (i.e., decreased glucose transport across the cell membrane in response to insulin).
  • pharmaceutically acceptable carrier or adjuvant refers to a non-toxic carrier or adjuvant that may be administered to a patient together with a compound of the invention, and which does not destroy the pharmacological activity thereof.
  • polycystic ovarian syndrome refers to a disease affecting women. Women diagnosed with PCOS may exhibit one or more of the following symptoms: anovulation (irregular or absent menstrual periods), hyperandrogenism (elevated serum testosterone and/or androstenedione), abnormal uterine bleeding, enlarged multifollicular ovaries, infertility, obesity, insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, type-2 0 diabetes mellitus, excess facial hair growth, hair loss, and acne.
  • anovulation irregular or absent menstrual periods
  • hyperandrogenism elevated serum testosterone and/or androstenedione
  • abnormal uterine bleeding enlarged multifollicular ovaries
  • infertility obesity, insulin resistance, hyperinsulinemia, hypertension, hyperlipidemia, type-2 0 diabetes mellitus, excess facial hair growth, hair loss, and acne.
  • therapeutically or pharmaceutically effective refers to an amount of the compound of this invention required to reduce or lessen the severity of PCOS or any of its symptoms (e.g., of insulin resistance, hyperinsulinemia, type-2 diabetes mellitus, obesity, hypertension, hyperlipidemia, 5 anovulation or irregular ovulation, infertility, hyperandrogenism, hirsutism, alopecia, acne, enlarged multifollicular ovaries and abnormal uterine bleeding, for some period of time).
  • a therapeutically or pharmaceutically effective amount also means the amount required to improve the clinical symptoms of a patient.
  • type-2 diabetes mellitus refers to a disease, also known as .0 non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes mellitus (AODM), in which a patient has elevated concentrations of blood sugar levels.
  • NIDDM non-insulin-dependent diabetes mellitus
  • AODM adult-onset diabetes mellitus
  • the present invention relates to methods for treating PCOS in a patient.
  • the methods include administering to a subject a therapeutically effective amount of GLP-1, exendin, and agonists and analogs of these compounds.
  • the methods of this invention further relate to -5 lowering insulin resistance using GLP-1, exendin, and agonists and analogs of these compounds.
  • Many of the symptoms associated with PCOS stem from an underlying insulin resistance.
  • GLP-1 plays a key role in the regulation of plasma glucose homeostasis. It is
  • GLP- 1 is a member of the incretin group of secretagogue hormones that are released from intestinal enteroendocrine cells in response to the ingestion of food.
  • GLP-1 binds to the GLP-1 receptor, which is expressed on the ⁇ -cells of the pancreas. Binding of GLP-1 to its receptor triggers an intracellular signaling pathway that results in stimulation of insulin 5 secretion with concomitant inhibition of glucagon production. This in turn leads to inhibition of hepatic glucose production, which lowers blood glucose levels.
  • GLP-1 (1-37) has the sequence: His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-Gly- Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp- Leu-Nal-Lys-Gly-Arg-Gly [SEQ ID NO: 1].
  • GLP-l(l-37) is amidated post-translationally to yield GLP-1(1-36)NH 2 , which has the sequence: His-Asp-Glu-Phe-Glu-Arg-His-Ala-Glu-
  • GLP-1 (7-37) which has the sequence: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser- Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly [SEQ ID NO: 3].
  • GLP-l(7-37) can also be amidated to yield GLP-1 (7-36)amide, which has the
  • GLP- l(l-36)amide can be processed to GLP-l(7-36)amide.
  • GLP-l(9-37) which has the sequence: Glu-Gly-Thr-Phe-Thr-Ser-Asp-Nal-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile- Ala-Trp-Leu-Nal-Lys-Gly-Arg-Gly [SEQ ID NO: 5], and GLP-1 (9-36)amide, which has the sequence: Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys- Glu-Phe-Ile-Ala-Trp-Leu-Nal-Lys-Gly-Arg(NH 2 ) [SEQ ID NO: 6], respectively. It has been 0 speculated that the peptide
  • GLP-1 analog includes GLP-l(l-37), GLP- 1(1-36)NH 2 , GLP-l(7-37), GLP-l(9-37), GLP-1 (9-36)NH 2 ("GLP-l(9-36)amide").
  • the present invention includes the use of recombinant human GLP-1 analogs and GLP-1 analogs derived from other species, whether recombinant or synthetic.
  • GLP-1 agonist includes any molecules, whether they be peptides, peptide mimetics, or other chemical compounds, that bind to or activate a GLP-1 receptor or receptors at which GLP-1 exerts its affect on PCOS, such as the GLP-1 (7-36)amide receptor, and its second messenger cascade.
  • GLP-1 agonists include molecules having insulinotropic activity and that are agonists of (i.e., activate) the GLP-1 receptor molecule and its second messenger activity on, inter alia, insulin producing ⁇ -cells.
  • GLP-1 analogs also include peptides that are encoded by polynucleotides that express biologically active GLP-1 analogs with agonist activity, as defined herein.
  • GLP-1 analogs may be peptides containing one or more amino acid substitutions, additions or deletions, compared with GLP-1 (7-36)amide.
  • the number of substitutions, deletions, or additions is 30 amino acids or less, 25 amino acids or less, 20 amino acids or less, 15 amino acids or less, 10 amino acids or less, 5 amino acids or less or any integer in between these amounts.
  • the substitutions include one or more conservative substitutions.
  • a "conservative" substitution denotes the replacement of an amino acid residue by another, biologically active similar residue.
  • conservative substitutions include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine, or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, and the like.
  • substitution of one hydrophobic residue such as isoleucine, valine, leucine, or methionine for another
  • one polar residue such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, and the like.
  • GLP-1 analogs include the above described peptides which have been chemically derivatized or altered, for example, peptides with non-natural amino acid residues (e.g., taurine, ⁇ - and ⁇ -amino acid residues and D-amino acid residues), C-terminal functional group modifications, such as amides, esters, and C-terminal ketone modifications and N-terminal functional group modifications, such as acylated amines, Schiff bases, or cyclization, as found, for example, in the amino acid pyroglutamic acid.
  • non-natural amino acid residues e.g., taurine, ⁇ - and ⁇ -amino acid residues and D-amino acid residues
  • C-terminal functional group modifications such as amides, esters
  • C-terminal ketone modifications such as acylated amines, Schiff bases, or cyclization, as found, for example, in the amino acid pyroglutamic acid.
  • sequence identity refers to a comparison made between two molecules using standard algorithms well known in the art.
  • the preferred algorithm for calculating sequence identity for the present invention is the Smith- Waterman algorithm, where SEQ ID NO: 1 [i.e., GLP-l(l-37)] is used as the reference sequence to define the percentage identity of homologs over its length.
  • SEQ ID NO: 1 i.e., GLP-l(l-37)
  • the choice of parameter values for matches, mismatches, and insertions or deletions is arbitrary, although some parameter values have been found to yield more biologically realistic results than others.
  • GLP-1 receptors a re c ell-surface p roteins found, for example, on insulin-producing pancreatic ⁇ -cells; the GLP-l(7-36) receptor has been characterised in the art. Methods of determining whether a chemical or peptide binds to or activates a GLP-1 receptor are known to the skilled artisan.
  • GLP-1 biological activity can be determined by in vitro and in vivo animal models and human studies, as is well known to the skilled artisan.
  • GLP-1 biological activity can be determined by standard methods, in general, by receptor binding activity screening procedures, which involve providing appropriate cells that express the GLP-1 receptor on their surface, for example, insulinoma cell lines such as R-NmSF cells or INS-1 0 cells. See Mojsov, Int. J. Peptide Protein Res. 40; 333 (1992) and EP 0708179 A2.
  • Cells that are engineered to express a GLP-1 receptor also can be used, hi addition to measuring specific binding of tracer to membrane using radioimmunoassay methods, cAMP activity or glucose dependent insulin production can also be measured, hi one method, a polynucleotide encoding the GLP-1 receptor is employed to transfect cells so that they express the GLP-1 receptor protein.
  • these methods may b e employed for s creening for a receptor agonist by c ontacting such c ells w ith c ompounds t o b e s creened and d etermining whether such compounds generate a signal (i.e., activate the receptor).
  • GLP-1 receptor for example, transfected CHO cells
  • a second messenger response e.g., signal transduction or ionic or pH changes
  • Polyclonal and monoclonal antibodies can be utilized to detect, purify, and identify GLP-1-like peptides for use in the methods described herein.
  • Antibodies such as ABGA1178 detect intact GLP-l(l-37) or N-terminally-truncated GLP-l(7-37) or GLP-1 (7-36)amide.
  • Other antibodies detect the end of the C-terminus of the precursor molecule, a procedure that allows one — by subtraction — to calculate the amount of biologically active, truncated peptide (i.e., GLP-1 (7-37)amide).
  • GLP-1 and the GLP-1 agonists of the invention that are peptides that can be made by solid-state chemical peptide synthesis. Such peptides can also be made by conventional recombinant techniques using standard procedures described in, for example, Sambrook & Maniatis, Molecular Cloning, A Laboratory Manual. "Recombinant,” as used herein, means that a gene is derived from a recombinant (e.g. , microbial or mammalian) expression system that has been genetically modified to contain a polynucleotide encoding a GLP-1 peptide as described herein.
  • a recombinant e.g. , microbial or mammalian
  • GLP-1 and the GLP-1 agonists of the invention that are peptides may be a naturally purified product, or a product of synthetic chemical procedures, or produced by recombinant techniques from prokaryotic or eukaryotic hosts (for example, by bacteria, yeast, higher plant, insect, or mammalian cells in culture or in vivo).
  • prokaryotic or eukaryotic hosts for example, by bacteria, yeast, higher plant, insect, or mammalian cells in culture or in vivo.
  • the polypeptides of the present invention are generally non-glycosylated, but may be glycosylated.
  • the GLP-1 peptides can be recovered and purified from recombinant cell cultures by methods including, but not limited to, ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, and lectin chromatography.
  • High- 5 performance liquid chromatography (HPLC) can be employed for final purification steps.
  • Exendin-4 a 39-amino acid polypeptide, is a naturally occurring peptide isolated from the salivary secretions of the Gila monster. Animal testing of exendin-4 has shown that its ability to lower blood glucose persists for several hours. Exendin-4, as it occurs in the 0 salivary secretions of the Gila monster, is an amidated peptide. However, it should be understood that the term “exendin,” and “exendin-4" specifically refers to both the amidated form of the peptide and the acid form of the peptide.
  • HSDAIFTQQYSKLLAKLALQKYLASILGSRTSPPP( H 2 ) 5 a GLP-l(7-36) (NH 2 ) [SEQ. ID NO: 4].
  • b exendin 3 (NH 2 ) [SEQ. ID NO: 7].
  • c exendin 4 (9-39)(NH 2 ) [SEQ. ID NO: 8].
  • d exendin 4 (NH 2 ) [SEQ. ID NO: 9].
  • 0 f helospectin II [SEQ. ID NO: 11].
  • g helodermin (NH 2 ) [SEQ. ID NO: 12].
  • h Q 8 , Q 9 helodermin (NH 2 ) [SEQ. ID NO: 13].
  • exendin-4 As described herein, the nonclinical pharmacology of exendin-4 has been studied, hi 5 the brain, exendin-4 binds principally to the area postrema and nucleus tractus solitarius region in the hindbrain and to the subfornical organ in the forebrain. Exendin-4 binding has been observed in the rat and mouse brain and kidney. The structures to which exendin-4 binds in the kidney are unknown.
  • Various experiments have compared the biologic actions of exendin-4 and GLP-1 and demonstrated a more favorable spectrum of properties for exendin-4. A single subcutaneous dose of exendin-4 lowered plasma glucose in db/db (diabetic) and ob/ob (diabetic obese) mice by up to 40%.
  • HbA ⁇ c a measure of glycosylated hemoglobin used to evaluate plasma glucose levels
  • exendin-4 An insulinotropic action of exendin-4 has also been observed in rodents, improving 0 insulin response to glucose by over 100% in non-fasted Harlan Sprague Dawley (HSD) rats, and by up to ⁇ 10-fold in non-fasted db/db mice. Higher pretreatment plasma glucose concentrations were associated with greater glucose-lowering effects. Thus the observed glucose lowering effect of exendin-4 appears to be glucose-dependent, and minimal if animals are already euglycemic.
  • Exendin-4 dose dependently slowed gastric emptying in HSD rats and was ⁇ 90-fold more potent than GLP-1 for this action. Exendin-4 has also been shown to reduce food intake in NIH/Sw (Swiss) mice following peripheral administration, and was at least 1000 times more potent than GLP-1 for this action. Exendin-4 reduced plasma glucagon concentrations by approximately 40% in anesthetized ZDF rats during hyperinsulinemic,
  • exendin-4 has been investigated in single-dose studies in mice, rats 5 and monkeys, repeated-dose (up to 28 consecutive daily doses) studies in rats and monkeys and in vitro tests for mutagenicity and chromosomal alterations. T o date, no deaths have occurred, and there have been no observed treatment-related changes in hematology, clinical chemistry, or gross or microscopic tissue changes. Exendin-4 was demonstrated to be non- mutagenic, and did not cause chromosomal aberrations at the concentrations tested (up to 0 5000 ⁇ g/mL). In support of the investigation of the nonclinical pharmacokinetics and metabolism of exendin-4, a number of immunoassays have been developed.
  • exendin agonist includes any molecules, whether they be peptides, peptide mimetics, or other chemical compounds, that bind to or
  • exendin agonists include molecules having insulinotropic activity and that are agonists of (i.e., activate) the GLP-1 receptor molecule and its second messenger activity on, inter alia, insulin producing ⁇ -cells.
  • exendin agonists include exendin analogs with agonist activity in which one or
  • exendin analogs are peptide analogs of exendin-4.
  • Exendin analogs include peptides that are encoded by polynucleotides that express biologically a ctive e xendin a nalogs w ith a gonist a ctivity, as d efined h erein.
  • exendin analogs may be peptides containing one or more amino acid substitutions, additions 0 or deletions, compared with exendin-4.
  • the number of substitutions, deletions, or additions is 30 amino acids or less, 25 amino acids or less, 20 amino acids or less, 15 amino acids or less, 10 amino acids or less, 5 amino acids or less or any integer in between these amounts.
  • the substitutions include one or more conservative substitutions.
  • a “conservative” substitution denotes the replacement of an amino acid residue by another, biologically active similar residue.
  • conservative substitutions include the substitution of one hydrophobic residue, such as isoleucine, valine, leucine, or methionine for another, or the substitution of one polar residue for another, such as the substitution of arginine for lysine, glutamic for aspartic acids, or glutamine for asparagine, and the like.
  • the following table lists illustrative, but non-limiting, conservative amino acid substitutions.
  • exendin analogs include the above described peptides which have been chemically derivatized or altered, for example, peptides with non-natural amino acid residues (e.g., taurine, ⁇ - and ⁇ -amino acid residues and D-amino acid residues), C-terminal functional group modifications, such as amides, esters, and C-terminal ketone
  • sequence identity refers to a comparison made between two molecules using standard algorithms well known in the art.
  • the preferred algorithm for calculating sequence identity for the present invention is the Smith- Waterman algorithm, where SEQ ID NO: 9 [i.e., exendin-4] is used as the reference sequence to define the percentage identity of homologs over its length.
  • parameter values for matches, mismatches, and insertions or deletions is arbitrary, although some parameter values have been found to yield more biologically realistic results than others.
  • Novel exendin analogs with agonist activity are described in commonly owned PCT Application Serial No. PCT/US98/16387 filed August 6, 1998, entitled “Novel Exendin Agonist Compounds,” which claims the benefit of U.S. Patent Application Serial No. 60/055,404, filed August 8, 1997, both of which are herein incorporated by reference.
  • Other novel exendin analogs with agonist activity are described in commonly owned
  • exendin agonists and exendin analogs with agonist activity can be indicated, for example, by activity in the assays described below. Effects of exendins or exendin agonists on PCOS can be identified, evaluated, or screened for, using the methods described herein, or other art-known or equivalent methods for determining effect on PCOS. 0 Negative receptor assays or screens for exendin agonist compounds or candidate exendin agonist compounds, such as a GLP-1 receptor assay/screen described above, an amylin receptor assay/screen using an amylin receptor preparation as described in U.S. Patent No.
  • one or more calcitonin receptor assays/screens using, for example, T47D and [5 MCF7 breast carcinoma cells, which contain calcium receptors coupled to the stimulation of adenyl cyclase activity, and/or a CGRP receptor assay/screen using, for example, SK-N-MC cells.
  • exendin-4 (1-30) [SEQ ID NO 14: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys -0 Gin Met Glu Glu Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys Asn Gly Gly] ; exendin-4 (1-30) amide [SEQ ID NO 15: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys Asn Gly Gly-NH 2 ]; exendin-4 (1-28) amide [SEQ ID NO 16: His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys Asn-NH 2 ]; 25 14 Leu, 25 Phe exendin-4 amide [SEQ ID NO 17: His Gly Glu Gly Thr Phe Thr Ser
  • compositions including said compounds and salts thereof.
  • Exendin analogs with agonist activity also include those described in U.S. Provisional Apphcation No. 60/065,442, including compounds of the formula (I) [SEQ ID NO. 20]:
  • Xaai Xaa Xaa 3 Gly Xaa 5 Xaa 6 Xaa Xaa 8 Xaa Xaaio Xaan Xaa ⁇ 2 Xaa ⁇ 3 Xaa ⁇ 4 Xaa ⁇ 5 Xaa ⁇ 6 Xaan Ala Xaa ⁇ 9 Xaa 2 o Xaa 2 ⁇ Xaa 22 Xaa 23 Xaa 24 Xaa 25 Xaa 26 Xaa 27 Xaa 28 -Z 1 ;
  • Xaai is His, Arg or Tyr
  • Xaa 2 is Ser, Gly, Ala or Thr;
  • Xaa 3 is Asp or Glu
  • Xaa 5 is Ala or Thr
  • Xaa 6 is Ala, Phe, Tyr or naphthylalanine
  • Xaa 7 is Thr or Ser
  • Xaa 8 is Ala, Ser or Thr;
  • Xaa 9 is Asp or Glu
  • Xaaio is Ala, Leu, He, Val, pentylglycine or Met;
  • Xaan is Ala or Ser
  • Xaa ⁇ is Ala or Lys
  • Xaa ⁇ 3 is Ala or Gin
  • Xaa ⁇ 4 is Ala, Leu, He, pentylglycine, Val or Met;
  • Xaa ⁇ 5 is Ala or Glu
  • Xaa ⁇ 6 is Ala or Glu
  • Xaan s Ala or Glu; Xaa ⁇ is Ala or Val;
  • Xaa 2 o is Ala or Arg
  • Xaa 2 ⁇ is Ala or Leu
  • Xaa 22 is Ala, Phe, Tyr or naphthylalanine
  • Xaa 23 is He, Val, Leu, pentylglycine, tert-butylglycine or Met;
  • Xaa 24 is Ala, Glu or Asp
  • Xaa 25 is Ala, Trp, Phe, Tyr or naphthylalanine
  • Xaa 26 is Ala or Leu
  • Xaa 27 is Ala or Lys
  • Xaa 28 is Ala or Asn
  • Xaa 3 ⁇ , Xaa 36 , Xaa 3 and Xaa 38 are independently Pro,homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; and
  • Z 2 is -OH or -NH 2 ; provided that no more than three of Xaa , Xaa 5 , Xaa 6 , Xaa 8 , Xaaio, Xaan, Xaa ⁇ 2 , Xaa ⁇ 3 , Xaa ⁇ 4 , Xaa ⁇ 5 , Xaa ⁇ 6 , Xaan, Xaa ⁇ , Xaa 2 o, Xaa 2 ⁇ , Xaa 24 , Xaa 25 , Xaa 26 , Xaa 2 and Xaa 28 are Ala.
  • N-alkyl groups for N-alkylglycine, N-alkylpentylglycine and N-alkylalanine include lower alkyl groups preferably of 1 to about 6 carbon atoms, more preferably of 1 to 4 carbon atoms.
  • Preferred exendin analogs include those wherein Xaai is His or Tyr. More preferably
  • Preferred compounds are those where Xaa 6 is Phe or naphthylalanine; Xaa 2 is Phe or naphthylalanine and
  • Xaa 23 is He or Val.
  • Xaa 3 ⁇ , Xaa 36 , Xaa 7 and Xaa 38 are independently selected from Pro, homoproline, thioproline and N-alkylalanine.
  • Zi is -NH 2 .
  • Z 2 is -NH 2 .
  • Xaa is His or Tyr, more preferably His;
  • Xaa 2 is Gly;
  • Xaa 6 is Phe or naphthylalanine;
  • Xaa ⁇ is Leu, pentylglycine or Met;
  • Xaa 22 is Phe or naphthylalanine;
  • Xaa 23 is He or Val;
  • Xaa and Xaa 38 are independently selected from Pro, homoproline, thioproline or N- alkylalanine. More preferably Zi is -NH 2 .
  • especially preferred compounds include those of formula (I) wherein: Xaai is His or Arg; Xaa 2 is Gly or Ala; Xaa 3 is Asp or Glu; Xaa 5 is Ala or Thr; Xaa 6 is Ala, Phe or nephthylalaine; Xaa is Thr or Ser; Xaa 8 is Ala, Ser or
  • Xaa 9 is Asp or Glu
  • Xaaio is Ala, Leu or pentylglycine
  • Xaan is Ala or Ser
  • Xaa ⁇ 2 is Ala or Lys
  • Xaan is Ala or Gin
  • Xaa is Ala, Leu or pentylglycine
  • Xaa ⁇ 5 is Ala or Glu
  • Xaa ⁇ 6 is
  • Xaan i Ala or Glu Ala or Glu
  • Xaa ⁇ 9 is Ala or Val
  • Xaa 20 is Ala or Arg
  • Xaa 2 ⁇ is Ala or Leu;
  • Especially preferred compounds include those set forth in PCT application Serial No. PCT/US98/24210, filed November 13, 1998, entitled “Novel Exendin Agonist Compounds” identified therein as compounds 2-23. 5 According to an especially preferred aspect, provided are compounds where Xaa ⁇ 4 is
  • Xaa 25 is Phe, Tyr or naphthylalanine, more preferably Phe or naphthylalanine.
  • Exendin analogs with agonist activity also include those described in U.S. Provisional Apphcation No. 60/066,029, including compounds of the formula (II)[SEQ ID NO. 21]:
  • Xaai is His, Arg, Tyr, Ala, Norval, Val or Norleu; -0 Xaa 2 is Ser, Gly, Ala or Thr;
  • Xaa 3 is Ala, Asp or Glu
  • Xaa 4 is Ala, Norval, Val, Norleu or Gly;
  • Xaa 5 is Ala or Thr
  • Xaa 6 is Phe, Tyr or naphthylalanine; 25 Xaa 7 is Thr or Ser;
  • Xaa 8 is Ala, Ser or Thr;
  • Xaa 9 is Ala, Norval, Val, Norleu, Asp or Glu;
  • Xaan is Ala or Ser; 0 Xaa ⁇ 2 is Ala or Lys;
  • Xaa ⁇ 3 is Ala or Gin;
  • Xaa ⁇ 4 is Ala, Leu, He, pentylglycine, Val or Met;
  • Xaa ⁇ 5 is Ala or Glu;
  • Xaa ⁇ 6 is Ala or Glu;
  • Xaan is Ala or Glu;
  • 5 Xaa ⁇ 9 is Ala or Val;
  • Xaa o is Ala or Arg; , Xaa 2 ⁇ is Ala or Leu; Xaa 22 is Phe, Tyr or naphthylalanine;
  • Xaa 2 is He, Val, Leu, pentylglycine, tert-butylglycine or Met;
  • 0 Xaa 24 is Ala, Glu or Asp;
  • Xaa 25 is Ala, Trp, Phe, Tyr or naphthylalanine;
  • Xaa 26 is Ala or Leu;
  • Xaa 2 is Ala or Lys;
  • Xaa 3 ⁇ , Xaa 36 , Xaa 37 and Xaa 38 are independently Pro,homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine; and 0 Z 2 is -OH or -NH 2 ; provided that no more than three of Xaa 3 , Xaa 4 , Xaa 5 , Xaa 6 , Xaa 8 , Xaa 9 , Xaaio, Xaan, Xaan, Xaa ⁇ 3 , X
  • N-alkyl groups for N-alkylglycine, N-alkylpentylglycine and N-alkylalanine include lower alkyl groups preferably of 1 to about 6 carbon atoms, more preferably of 1 to 4 carbon atoms.
  • Suitable compounds of formula (II) include those described in application Serial No. PCT/US 98/24273, filed November 13, 1998, entitled “Novel Exendin Agonist Compounds", identified therein in Examples 1-89 ("Compounds 1-89,” respectively), as well as those corresponding compounds identified therein in Examples 104 and 105.
  • Preferred such exendin analogs include those wherein Xaai is His, Ala or Norval. More preferably Xaai is His or Ala. Most preferably Xaai is His.
  • Preferred compounds of formula (II) are those wherein Xaa 25 is Trp or Phe.
  • Preferred compounds of formula (II) are those where Xaa 6 is Ala, Phe or naphthylalanine; Xaa 22 is Phe or naphthylalanine; and Xaa 23 is He or Val.
  • Z . is -NH 2 .
  • Z 2 is -NH 2 .
  • Xaai is Ala, His or Tyr, more preferably Ala or His
  • Xaa 2 is Ala or Gly
  • Xaa 6 is Phe or naphthylalanine
  • Xaa ⁇ 4 is Ala, Leu, pentylglycine or Met
  • Xaa 22 is Phe or naphthylalanine
  • Xaa 23 is He or Val
  • Xaa 3 ⁇ , Xaa 36 , Xaa 37 and Xaa 8 are independently selected from Pro, homoproline, t hioproline o r N -alkylalanine
  • X aa 39 i s S er o r T yr, more preferably Ser.
  • especially preferred compounds include those of formula (II) wherein: Xaai is His or Ala; Xaa 2 is Gly or Ala; Xaa is Ala, Asp or Glu; Xaa 4 is Ala or Gly; Xaa 5 is Ala or Thr; Xaa 6 is Phe or naphthylalanine; Xaa is Thr or Ser; Xaa 8 is Ala, Ser or Thr; Xaa 9 is Ala, Asp or Glu; Xaaio i Ala, Leu or pentylglycine; Xaan is Ala or Ser; Xaa ⁇ is Ala or Lys; Xaa ⁇ 3 is Ala or Gin; Xaa ⁇ 4 i s Ala, Leu, M et or pentylglycine; Xaa ⁇ 5 is Ala or Glu; Xaa ⁇ 6 is Al
  • Especially preferred compounds of formula (II) include those described in application Serial No. PCT/US98/24273, filed November 13, 1998, entitled “Novel Exendin Agonist Compounds” as having the amino acid sequence of SEQ. ID. NOS. 5-93 therein.
  • Xaa ⁇ 4 is Ala, Leu, He, Val or pentylglycine, more preferably Leu or pentylglycine
  • Xaa 25 is Ala, Phe, Tyr or naphthylalanine, more preferably Phe or naphthylalanine.
  • narrower genera of compounds having peptides of various lengths for example genera of compounds which do not include peptides having a length of 28, 29 or 30 amino acid residues, respectively. Additionally, the present invention includes narrower genera of compounds described in PCT application
  • Xaai Xaa Xaa 3 Gly Xaa 5 Xaa 6 Xaa 7 Xaa 8 Xaa 9 Xaaio Xaan Xaa ⁇ 2 Xaa ⁇ 3 Xaau Xaais Xaa ]6 Xaan Ala Xaa ⁇ 9 Xaa 2 oXaa 2 ⁇ Xaa 2 Xaa 23 Xaa 24 Xaa 25 Xaa 26 Xaa 27 Xaa 28 -Z ⁇ ;
  • Xaa 2 is Gly or Ala
  • Xaa 3 is Asp or Glu
  • Xaa 5 is Ala or Thr
  • Xaa 6 is Ala, Phe or naphthylalanine
  • Xaa 7 is Thr or Ser
  • Xaa 8 is Ala, Ser or Thr;
  • Xaa is Asp or Glu
  • Xaaio is Ala, Leu or pentylglycine
  • Xaan is Ala or Ser
  • Xaa is Ala or Lys
  • Xaa ⁇ 3 is Ala or Gin
  • Xaa ⁇ 4 is Ala, Leu or pentylglycine
  • Xaa ⁇ 6 is Ala or Glu
  • Xaan is Ala or Glu
  • Xaa ⁇ 9 is Ala or Val
  • Xaa 2 o is Ala or Arg
  • Xaa ⁇ is Ala or Leu
  • Xaa 2 is Phe or naphthylalanine
  • Xaa 23 is He, Val or tert-butylglycine
  • Xaa 2 is Ala, Glu or Asp
  • Xaa 25 is Ala, Trp, or Phe; Xaa 26 is Ala or Leu; Xaa 27 is Ala or Lys; Xaa 28 is Ala or Asn; Zi is -OH, 5 -NH 2 ,
  • Gly-Z 2 Gly Gly -Z 2 , Gly Gly -Z 2 , Gly Gly Xaa 3 ⁇ -Z 2 , Gly Gly Xaa 3 ⁇ Ser-Z 2 , .0 Gly Gly Xaa 3 ⁇ Ser Ser-Z 2 ,
  • Xaa 3 ⁇ , Xaa 6 , Xaa and Xaa 8 are independently selected from the group consisting of Pro, homoproline, thioproline and N-methylylalanine; and Z 2 is -OH or -NH 2 ; provided that no more than three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 8 , Xaaio, Xaan, X an, 20 X a ⁇ 3 , Xaa ⁇ 4 , Xaa ⁇ 5 , Xaa ⁇ 6 , Xaan, Xaa ⁇ 9 , Xaa 2 o, Xaa 2 ⁇ , Xaa 24 , Xaa 25 , Xaa 6 , Xaa 2 and Xaa 28 are Ala; and pharmaceutically acceptable salts thereof.
  • the present invention includes narrower genera of peptide compounds described in PCT Application Serial No. PCT/US98/24273, filed November 13, 1998, 5 entitled “Novel Exendin Agonist Compounds" as having particular amino acid sequences, for example, compounds of the formula [IV] [SEQ. ID. NO. 23]:
  • Xaai is His or Ala
  • Xaa 2 is Gly or Ala
  • Xaa 3 is Ala, Asp or Glu
  • Xaa 5 is Ala or Thr
  • Xaa 6 is Phe or naphthylalanine
  • Xaa is Thr or Ser
  • Xaa 8 is Ala, Ser or Thr;
  • Xaa 9 is Ala, Asp or Glu
  • Xaaio is Ala, Leu or pentylglycine
  • Xaan is Ala or Ser
  • Xaan is Ala or Lys
  • Xaa ⁇ 3 is Ala or Gin
  • Xaa ⁇ 4 is Ala, Leu, Met or pentylglycine
  • Xaa ⁇ 6 is Ala or Glu
  • Xaan is Ala or Glu
  • Xaa ⁇ is Ala or Val
  • Xaa 20 is Ala or Arg
  • Xaa 2 ⁇ is Ala or Leu
  • Xaa 22 is Phe or naphthylalanine
  • Xaa 23 is He, Val or tert-butylglycine
  • Xaa 24 is Ala, Glu or Asp
  • Xaa 25 is Ala, Trp or Phe;
  • Xaa 26 is Ala or Leu
  • Xaa 27 is Ala or Lys
  • Xaa 28 is Ala or Asn
  • Gly-Zz Gly Gly-Z 2 Gly Gly Xaa 3 ⁇ -Z 2 , Gly Gly Xaa 3 ⁇ Ser-Z 2 , Gly Gly Xaa 3i Ser Ser-Z 2 , Gly Gly Xaa 3 1 Ser Ser Gly-Z 2 ,
  • Xaa 3 ⁇ , Xaa 36 , Xaa 37 and Xaa 38 are independently Pro,homoproline, thioproline, or N-methylylalanine;
  • Z 2 is -OH or -NH 2 ; provided that no more than three of Xaa , Xaa 5 , Xaa 6 , Xaa 8 , Xaaio, Xaan, Xaa , Xaa , Xaa ⁇ 4 , Xaa ⁇ 5 , Xaa ⁇ 6 , Xaan, Xaa ⁇ 9 , Xaa 2 o, Xaa ⁇ , Xaa 24 , Xaa 25 , Xaa 26 , Xaa 27 , and Xaa 28 are Ala; and provided that, if Xaai is His, Arg or Tyr, then at least one of Xaa 3 , Xaa 4 and Xaa 9 is Ala; and pharmaceutically acceptable salts thereof.
  • Preferred compounds of formula (IV) include those wherein Xaai is His, Ala, Norval or 4-imidazopropionyl.
  • Xaai is His, or 4-imidazopropionyl or Ala, more preferably His or 4-imidazopropionyl.
  • Preferred compounds of formula (IV) include those wherein Xaa2 is Gly.
  • Preferred compounds of formula (IV) include those wherein Xaa4 is Ala.
  • Preferred compounds of formula (IV) include those wherein Xaa9 is Ala.
  • Preferred compounds of formula (IN) include those wherein Xaai 4 is Leu, pentylglycine or Met.
  • Preferred compounds of formula (IV) include those wherein Xaa25 is Trp or Phe.
  • Preferred compounds of formula (IV) include those wherein Xaa6 is Ala, Phe or naphthylalanine; Xaa22 is Phe or naphthylalanine; and Xaa23 is He or Val.
  • Preferred compounds of formula (IV) include those wherein ZI is - ⁇ H2.
  • Preferred compounds of formula (IV) include those wherein Xaa31, Xaa36, Xaa37 and Xaa38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.
  • Preferred compounds of formula (IV) include those wherein Xaa39 is Ser or Tyr, preferably Ser.
  • Preferred compounds of formula (IV) include those wherein Z2 is -NH2.
  • Preferred compounds of formula (IV) include those 42 wherein ZI is -NH2.
  • Preferred compounds of formula (IV) include those wherein Xaa21 i s Lys-NHD-R where R is Lys, Arg, C1-C10 straight chain or branched alkanoyl.
  • Preferred compounds of formula (IV) include those wherein XI is Lys Asn, Lys-
  • Preferred compounds of formula (IN) include those having an amino acid sequence described in PCT application Serial No. PCT/US98/24273, filed November 13, 1998, entitled “Novel Exendin Agonist Compounds" as being selected from SEQ. ID. NOS. 95-110 therein.
  • Xaai is His, Arg or Tyr or 4-imidazopropionyl
  • Xaa 2 is Ser, Gly, Ala or Thr;
  • Xaa 3 is Asp or Glu
  • Xaa 5 is Ala or Thr
  • Xaa 6 is Ala, Phe, Tyr or naphthylalanine;
  • Xaa 7 is Thr or Ser;
  • Xaa 8 is Ala, Ser or Thr; Xaa 9 is Asp or Glu;
  • Xaaio is Ala, Leu, He, Nal, pentylglycine or Met; Xaan is Ala or Ser; Xaan is Ala or Lys; Xaan is Ala or Gin;
  • Xaa ⁇ 4 is Ala, Leu, He, pentylglycine, Nal or Met;
  • Xaa ⁇ 5 is Ala or Glu;
  • Xaa ⁇ 6 is Ala or Glu;
  • Xaan is Ala or Glu;
  • Xaa ⁇ 9 is Ala or Nal;
  • Xaa 2 o is Ala or Arg;
  • Xaa 2 ⁇ is Ala, Leu or Lys- ⁇ H ⁇ -R where R is Lys, Arg, Ci-Cio straight chain or branched alkanoyl or cycloalkylalkanoyl;
  • Xaa 22 is Phe, Tyr or naphthylalanine
  • Xaa 23 is He, Val, Leu, pentylglycine, tert-butylglycine or Met;
  • Xaa 24 is Ala, Glu or Asp;
  • Xaa 5 is Ala, Trp, Phe, Tyr or naphthylalanine;
  • Xaa 26 is Ala or Leu;
  • Xi is Lys Asn, Asn Lys, Lys-NH ⁇ -R Asn, Asn Lys-NH ⁇ -R, Lys-NH ⁇ -R Ala, Ala Lys- NH ⁇ -R where R is Lys, Arg, Ci-Cio straight chain or branched alkanoyl or cycloalkylalkanoyl Zi is -OH,
  • Xaa 3 ⁇ , Xaa 36 , Xaa 37 and Xaa 8 are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N- alkylpentylglycine and N-alkylalanine; and Z 2 is -OH or -NH 2 ; provided that no more than three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 8 , Xaaio, Xaan, Xaan,
  • Xaan, Xaa ⁇ 4 , Xaan, Xaa ⁇ 6 , Xaan, X a ⁇ 9 , Xaa 2 o, Xaa 2 ⁇ , Xaa 24 , Xaa 2 , and Xaa 26 are Ala.
  • pharmaceutically acceptable salts of the compound of formula (V) and pharmaceutical compositions including said compounds and salts thereof are also within the scope of the present invention.
  • Preferred exendin analogs of formula (V) include those wherein Xaai is His, Tyr or 4- imidazopropionyl. More preferably Xaai is His.
  • Preferred compounds of formula (V) are those wherein Xaa 25 is Trp or Phe. According to one a spect, preferred are compounds of formula (V) wherein X aa 6 i s Phe or naphthylalanine; and Xaa 22 is Phe or naphthylalanine; and Xaa 23 is He or Val. More preferably, Zi is -NH 2 . According to one aspect, especially preferred are such compounds of formula (V) wherein Xaa 3 ⁇ , Xaa 36 , Xaa 37 and Xaa 38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine. More preferds, Z 2 is - NH 2 .
  • Preferred compounds of formula (V) include those wherein Xi is Lys Asn, Lys-NH ⁇ - R Asn, or Lys-NH ⁇ -R Ala where R is Lys, Arg, Ci-Cio straight chain or branched alkanoyl.
  • Preferred compounds of formula (V) include compounds described in PCT application Serial
  • Preferred such exendin analogs include those wherein Xaai is His, Ala or Norval. More preferably Xaai is His or Ala. Most preferably Xaai is His.
  • Preferred compounds of formula (V) are those wherein Xaa 5 is Trp or Phe.
  • Preferred compounds of formula (V) are those where Xaa 6 is Ala, Phe or naphthylalanine; Xaa 22 is Phe or naphthylalanine; and Xaa 23 is He or Val.
  • Z ⁇ is -NH 2 .
  • Z 2 is -NH 2 .
  • Xaai i s Ala, His or Tyr more preferably Ala or His
  • Xaa 2 is Ala or Gly
  • Xaa 6 is Phe or [5 naphthylalanine
  • Xaa ⁇ 4 is Ala, Leu, pentylglycine or Met
  • Xaa 22 is Phe or naphthylalanine
  • Xaa 23 is He or Val
  • Xaa 3 ⁇ , Xaa 6 , Xaa 3 and Xaa 38 are independently selected from Pro, homoproline, t hioproline o r N -alkylalanine
  • X aa 3 i s S er o r T yr more preferably Ser. More preferably Zi is -NH 2 .
  • especially preferred compounds include
  • Xaa 8 is Ala, Ser or Thr
  • Xaa 9 is Ala, Asp or Glu
  • Xaaio is Ala, Leu or pentylglycine
  • Xaan is Ala or Ser; Xaan is Ala or Lys; Xaan is Ala or Gin; Xaa ⁇ 4 is Ala, Leu, M et or pentylglycine; Xaan is Ala or Glu; Xaa ⁇ 6 is Ala or Glu; Xaan is Ala or Glu; Xaa ⁇ 9 is Ala or
  • Xaa 2 o is Ala or Arg
  • Xaa ⁇ is Ala or Leu
  • Xaa 22 is Phe or naphthylalanine
  • Xaa 2 is He
  • Xaa 24 is Ala, Glu or Asp
  • Xaa 25 is Ala, Trp or Phe
  • Xaa 6 is Ala or
  • Xaa 27 is Ala or Lys
  • Xaa 28 is Ala or Asn
  • Zi is -OH, -NH 2 , Gly-Z 2 , Gly Gly-Z 2 , Gly Gly
  • Xaa ⁇ 4 , Xaan, Xaa ⁇ 6 , Xaan, Xaa ⁇ 9 , Xaa 2 o, Xaa ⁇ , Xaa 24 , X aa 25 , Xaa 26 , Xaa 27 and Xaa 28 are
  • Agonist Compounds and having the amino acid sequences identified therein as SEQ. ID.
  • Xaai 4 is Ala, Leu, He, Val or pentylglycine, more preferably Leu or pentylglycine
  • Xaa25 is Ala, Phe, Tyr or naphthylalanine, more preferably Phe or naphthylalanine.
  • Xaai is His, Arg, Tyr, Ala, Norval, Val, Norleu or 4-imidazopropionyl
  • Xaa 2 is Ser, Gly, Ala or Thr;
  • Xaa 3 is Ala, Asp or Glu
  • Xaa 4 is Ala, Norval, Val, Norleu or Gly;
  • Xaa 5 is Ala or Thr
  • Xaa 8 is Ala, Ser or Thr;
  • Xaa 9 is Ala, Norval, Val, Norleu, Asp or Glu;
  • Xaaio is Ala, Leu, He, Val, pentylglycine or Met;
  • Xaan is Ala or Ser;
  • Xaan is Ala or Lys;
  • Xaan is Ala or Gin;
  • Xaa 2 o is Ala or Arg
  • Xaa 2 ⁇ is Ala, Leu or Lys-NH ⁇ -R where R is Lys, Arg, C 1"10 straight chain or branched alkanoyl or cycloalleyl-alkanoyl;
  • Xaa 22 is Phe, Tyr or naphthylalanine
  • Xaa 23 is He, Val, Leu, pentylglycine, tert-butylglycine or Met;
  • Xaa 4 is Ala, Glu or Asp
  • Xaa 25 is Ala, Trp, Phe, Tyr or naphthylalanine
  • Xaa 26 is Ala or Leu;
  • Xi is Lys Asn, Asn Lys, Lys-NH ⁇ -R Asn, Asn Lys-NH ⁇ -R, Lys-NH ⁇ -R Ala, Ala Lys- NH ⁇ -R where R is Lys, Arg, Ci- o straight chain or branched alkanoyl or cycloalkylalkanoyl Zi is -OH,
  • Xaa 3 ⁇ , Xaa 36 , Xaa 7 and Xaa 38 are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N- alkylpentylglycine and N-alkylalanine; and Z 2 is -OH or -NH 2 ; provided that no more than three of Xaa 3 , Xaa-i, Xaa 5 , Xaa 6 , Xaa 8
  • Preferred compounds of formula (VI) include those wherein Xaai is His, Ala, Norval or 4-imidazopropionyl.
  • Xaai is His, or 4-imidazopropionyl or Ala, more preferably His or 4-imidazopropionyl.
  • Preferred compounds of formula (VI) include those wherein Xaa 2 is Gly.
  • Preferred compounds of formula (VI) include those wherein Xaa 4 is Ala.
  • Preferred compounds of formula (VI) include those wherein Xaa is Ala.
  • Preferred compounds of formula (VI) include those wherein Xaa ⁇ 4 is Leu, pentylglycine or Met.
  • Preferred compounds of formula (VI) include those wherein Xaa 25 is Trp or Phe.
  • Preferred compounds of formula (VI) include those wherein Xaa 6 is Ala, Phe or naphthylalanine; Xaa 22 is Phe or naphthylalanine; and Xaa 2 is He or Val.
  • Preferred compounds of formula (VI) include those wherein Z ⁇ is -NH 2 . .
  • Preferred compounds of formula (VI) include those wherein Xaa 3 ⁇ , Xaa 36 , Xaa 3 and Xaa 38 are independently selected from the group consisting of Pro, homoproline, thioproline and N-alkylalanine.
  • Preferred compounds of formula (VI) include those wherein Xaa 39 is Ser or Tyr, preferably Ser.
  • Preferred compounds of formula (VI) include those wherein Z 2 is -NH 2 .
  • Preferred compounds of formula (VI) include those 42 wherein Z ⁇ is -NH 2 .
  • Preferred compounds of formula (VI) include those wherein Xaa 2 ⁇ is Lys-NH ⁇ -R where R is Lys, Arg, Ci-Cio straight chain or branched alkanoyl.
  • Preferred compounds of formula (VI) include those wherein X ⁇ is Lys Asn, Lys-NH ⁇ - R Asn, or Lys-NH ⁇ -R Ala where R is Lys, Arg, Ci-Cio straight chain or branched alkanoyl.
  • Preferred compounds of formula (VI) include those described in PCT Application Serial No. PCT/US98/24273, filed November 13, 1998, entitled “Novel Exendin Agonist Compounds” as having an amino acid sequence selected from those identified therein as SEQ. ID. NOS. 95-110.
  • Xaa 2 is Ser, Gly, Ala or Thr;
  • Xaa 3 is Asp or Glu
  • Xaa 4 is Phe, Tyr or naphthalanine
  • Xaa 5 is Thr or Ser
  • Xaa 6 is Ser or Thr
  • Xaa is Asp or Glu
  • Xaa 8 is Leu, He, Val, pentylglycine or Met;
  • Xaa is Leu, He, pentylglycine, Val or Met;
  • Xaaio is Phe, Tyr or naphthalanine
  • Xaan is He, Val, Leu, pentylglycine, tert-butylglycine or Met;
  • Xaan is Glu or Asp; Xaan is Trp, Phe, Tyr, or naphthylalanine; Xaa ⁇ 4 , Xaan, X a ⁇ 6 and Xaa are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine;
  • N-alkyl groups for N-alkylglycine, N-alkylpentylglycine and N- alkylalanine include lower alkyl groups preferably of 1 to about 6 carbon atoms, more preferably of 1 to 4 carbon atoms. Also useful in the present invention are pharmaceutically acceptable salts of the compounds of formula (VII).
  • Preferred exendin analogs include those wherein Xaai is His or Tyr. More preferably
  • Preferred compounds include those wherein Xaan is Trp or Phe.
  • Xaa 4 is Phe or naphthalanine
  • Xaan is He or Val
  • Xaa ⁇ 4 , Xaan, X a ⁇ 6 and Xaan are independently selected from Pro, homoproline, thioproline or N-alkylalanine.
  • N-alkylalanine has a N-alkyl group of 1 to about 6 carbon atoms.
  • Xaan, Xaa ⁇ 6 and Xaan are the same amino acid reside.
  • Preferred are compounds wherein Xaan is Ser or Tyr, more preferably Ser.
  • Z is -NH 2 .
  • Xaa 2 is Gly;
  • Xaa 4 is Phe or naphthalanine;
  • Xaa 9 is Leu, pentylglycine or Met;
  • Xaaio is Phe or naphthalanine;
  • Xaan is He or Val;
  • Xaa ⁇ 4 , Xaan, Xaa ⁇ 6 and Xaan are independently selected from Pro, homoproline, thioproline or N-alkylalanine; and
  • Xaan is Ser or Tyr, more preferably Ser. More preferably Z is -NH 2 .
  • especially preferred compounds include those of formula (VII) wherein: Xaai is His or Arg; Xaa 2 is Gly; Xaa 3 is Asp or Glu; Xaa 4 is
  • Xaa 5 is Thr or Ser
  • Xaa 6 is Ser or Thr
  • Xaa 7 is Asp or Glu
  • Xaa 8 is Leu or pentylglycine
  • Xaa 9 is Leu or pentylglycine
  • Xaan is He
  • Xaan is Glu or Asp
  • Xaa is Trp or Phe
  • Xaaj 4 , Xaan, Xaan, and Xaan are independently Pro, homoproline, thioproline, or N-methylalanine
  • Xaan is Ser or Tyr: and Z is -OH or -NH 2 ; with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 7 or 9. More preferably Z is -NH 2 ..
  • Xaa 9 is Leu, He, Val or pentylglycine, more preferably Leu or pentylglycine
  • Xaan is Phe, Tyr or naphthylalanine, more preferably Phe or naphthylalanine.
  • Xaai is His, Arg, Tyr or 4-imidazopropionyl
  • Xaa 2 is Ser, Gly, Ala or Thr;
  • Xaa is Asp or Glu
  • Xaa 4 is Phe, Tyr or naphthylalanine
  • Xaa 5 is Thr or Ser
  • Xaa 6 is Ser or Thr
  • Xaa is Asp or Glu
  • Xaa 8 is Leu, He, Val, pentylglycine or Met;
  • Xaa 9 is Leu, He, pentylglycine, Val or Met;
  • Xaaio is Phe, Tyr or naphthylalanine
  • Xaan is He, Val, Leu, pentylglycine, tert-butylglycine or Met;
  • Xaan is Glu or Asp; Xaan is Trp, Phe, Tyr, or naphthylalanine; Xi is Lys Asn, Asn Lys, Lys-NH ⁇ -R Asn, Asn Lys-NH ⁇ -R where R is Lys, Arg, Ci-Cio straight chain or branched alkanoyl or cycloalkylalkanoyl;
  • Xaa ⁇ , Xaan, Xaa ⁇ 6 and Xaan are independently Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine or N-alkylalanine;
  • Xaan is Ser, Thr or Tyr; and Z is -OH or -NH 2 ; with the proviso that the compound does not have the formula of either SEQ. ID. NOS. 7 or 9.
  • Suitable compounds of formula (VIII) include compounds described in PCT Application Serial No. PCT/US98/16387, filed August 6, 1998, entitled “Novel Exendin Agonist Compounds" having the amino acid sequences of SEQ. ID. NOS. 37-40 therein.
  • Preferred exendin analogs of formula (VIII) include those wherein Xaai is His, Tyr or 4-imidazopropionyl. More preferably, Xaai is His or 4-imidazopropionyl.
  • Xi is Lys Asn, or Lys-NH ⁇ -R Asn, where R is Lys, Arg, Ci-Cio straight chain or branched alkanoyl.
  • compounds of formula (VIII) wherein Xaa 4 is Phe or naphthylalanine; Xaaio is Phe or naphthylalanine; Xaan is He or Nal and Xaan, Xaan, Xaan and Xaan are independently selected from Pro, homoproline, thioproline or ⁇ -alkylalanine.
  • Xaan is Ser or Tyr. Preferred are those such compounds wherein Xaan is Ser.
  • Z is - ⁇ H 2 .
  • exendins and exendin analogs of the invention do not include the peptides of SEQ ID NOS. 7-13.
  • preferred exendin analogs include the analogs of Formulas (I- VIE), with the proviso that the analogs do not include the peptides of SEQ ID NOs: 7-13.
  • Exendins and exendin agonists that are peptides, such as exendin analogs, described herein may be prepared through peptide purification as described in, for example, Eng, et al, J. Biol. Chem. 265:20259-62, 1990; and Eng, et al, J. Biol. Chem. 267:7402-05, 1992, hereby incorporated by reference herein.
  • exendins and exendin agonists that are peptides may be prepared by methods known to those skilled in the art, for example, as described in Raufman, et al, J. Biol. Chem.
  • the compounds that constitute active ingredients of the formulations and dosages of the present invention may be prepared using standard solid-phase peptide synthesis techniques and preferably an automated or semiautomated peptide synthesizer.
  • an ⁇ -N-carbamoyl protected amino acid and an amino acid attached to the growing peptide chain on a resin are coupled at room temperature in an inert solvent such as dimethylformamide, N- methylpyrrolidinone or methylene chloride in the presence of coupling agents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in the presence of a base such as diisopropylethylamine.
  • an inert solvent such as dimethylformamide, N- methylpyrrolidinone or methylene chloride
  • coupling agents such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole in the presence of a base such as diisopropylethylamine.
  • the ⁇ -N-carbamoyl protecting group is removed from the resulting peptide-resin using a reagent such as trifluoroacetic acid or piperidine, and the coupling reaction repeated with the next desired N-protected amino acid to be added to the peptide chain.
  • a reagent such as trifluoroacetic acid or piperidine
  • Suitable N-protecting groups are well known in the art, with t-butyloxycarbonyl (tBoc) and fluorenylmethoxycarbonyl (Fmoc) being preferred herein.
  • the solvents, amino acid derivatives and 4-methylbenzhydryl-amine resin used in the peptide synthesizer may be purchased from Applied Biosystems Inc. (Foster City, CA).
  • the following side-chain protected amino acids may be purchased from Applied Biosystems, Inc.: BSD-112344.
  • Boc-His(BOM) may be purchased from Applied B iosystems, Inc. or Bachem Inc. (Torrance, C A).
  • a nisole, dimethylsulf ⁇ de, phenol, ethanedithiol, and thioanisole may be obtained from Aldrich Chemical Company (Milwaukee, Wl). Air Products and Chemicals (Allentown, PA) supplies HF. Ethyl ether, acetic acid and methanol may be purchased from Fisher Scientific (Pittsburgh, PA).
  • Solid phase peptide synthesis may be carried out with an automatic peptide synthesizer (Model 430A, Applied Biosystems Inc., Foster City, CA) using the NMP/HOBt (Option 1) system and tBoc or Fmoc chemistry (see, Applied Biosystems User's Manual for the ABI 430A Peptide Synthesizer, Version 1.3B July 1, 1988, section 6, pp. 49-70, Applied Biosystems, Inc., Foster City, CA) with capping. Boc-peptide-resins may be cleaved with HF (-50°C to 0°C, 1 hour). The peptide may be extracted from the resin with alternating water and acetic acid, and the filtrates lyophilized.
  • an automatic peptide synthesizer Model 430A, Applied Biosystems Inc., Foster City, CA
  • NMP/HOBt Option 1
  • tBoc or Fmoc chemistry see, Applied Biosystems User's Manual
  • the Fmoc-peptide resins may be cleaved according to standard methods (Introduction to Cleavage Techniques, Applied Biosystems, Inc., 1990, pp. 6-12). Peptides may also be assembled using an Advanced Chem Tech Synthesizer (Model MPS 350, Louisville, Kentucky).
  • Peptides may be purified by RP-HPLC (preparative and analytical) using a Waters Delta Prep 3000 system.
  • a C4, C8 or C18 preparative column (10 ⁇ , 2.2 x 25 cm; Vydac, Hesperia, CA) may be used to isolate peptides, and purity may be determined using a C4, C8 or C18 analytical column (5 ⁇ , 0.46 x 25 cm; Vydac).
  • Amino acid analyses may be performed on the Waters Pico Tag system and processed using the Maxima program.
  • Peptides may be hydrolyzed by vapor-phase acid hydrolysis (115°C, 20-24 h). Hydrolysates may be derivatized and analyzed by standard methods (Cohen, et al., The Pico Tag Method: A Manual of Advanced Techniques for Amino Acid Analysis, pp. 11-52, Millipore Corporation, Milford, MA (1989)).
  • Fast atom bombardment analysis may be carried out by M-Scan, Incorporated (West Chester, PA).
  • Mass calibration may be performed using cesium iodide or cesium iodide/glycerol. Plasma desorption ionization analysis using time of flight detection may be carried out on an Applied Biosystems Bio-Ion 20 mass spectrometer. Electrospray mass spectroscopy may be carried and on a VG-Trio machine.
  • Exendins and exendin agonists that are peptides may also be prepared using recombinant DNA techniques, using methods now known in the art. See, e.g., Sambrook et al, Molecular Cloning: A Laboratory Manual, 2d Ed., Cold Spring Harbor (1989). Alternatively, such compounds may b e prepared by homogeneous phase peptide synthesis methods. Non-peptide compounds useful in the present invention may be prepared by art- known methods. For example, phosphate-containing amino acids and peptides containing such amino acids, may be prepared using methods known in the art. See, e.g., Bartlett and Landen, Biorg. Chem. 14:356-377 (1986).
  • the methods and compositions of this invention may be used to treat PCOS.
  • Many of the symptoms associated with PCOS stem from an underlying insulin resistance.
  • the symptoms associated with PCOS include insulin resistance, hyperinsulinemia, hyperandrogenism, type-2 diabetes mellitus, irregular menses, anovulation and infertility.
  • the present invention provides methods of treating insulin resistance in a subject suffering from PCOS comprising the step of administering GLP-1.
  • Insulin resistance may be due to any one or more events including abnormal prereceptor (e.g., abnormal ligand or competition), receptor (e.g., abnormal structure, affinity of ligand to receptor, or number of receptors), or postreceptor (e.g., abnormal signaling)
  • abnormal prereceptor e.g., abnormal ligand or competition
  • receptor e.g., abnormal structure, affinity of ligand to receptor, or number of receptors
  • postreceptor e.g., abnormal signaling
  • Insulin resistance may be determined by a number of methods known in the art.
  • the euglycemic hyperinsulinemic clamp technique may be used to diagnose insulin resistance (Rao, G., Am. Fam. Physician (2001) 63:1159-63). This technique involves intravenous administration of an insulin dose while simultaneously maintaining glucose at a pre-set level within the normal range by also administering glucose. At equilibrium, the
  • glucose uptake by a particular tissue in the presence of a certain dose of insulin can be calculated.
  • Other methods used to detect insulin resistance include the insulin suppression test, intravenous glucose tolerance test, and constant infusion of glucose with model assessment (Rao, G., supra).
  • the invention provides a method of preventing the onset of
  • Type-2 diabetes mellitus in a subject suffering from PCOS comprising the step of administering GLP-1, exendin, or agonists or analogs of these compounds.
  • Type-2 diabetes mellitus is often a result of hyperinsulinemia caused by insulin resistance. Thus, treating insulin resistance in these patients would prevent the development of type-2 diabetes mellitus.
  • Methods of diagnosing type-2 diabetes mellitus are well-known in the art.
  • this invention provides a method of restoring regular menses, restoring regular ovulation and/or restoring fertility in a subject suffering from PCOS comprising the step of administering GLP-1, exendin, or agonists or analogs of these compounds.
  • PCOS patients often exhibit hyperandrogenism, which is thought to be caused by hyperinsulinemia. The hyperandrogenism leads to follicular involution, anovulation and infertility.
  • reducing insulin resistance by administering GLP-1, exendin, or agonists or analogs of these compounds can ameliorate hyperinsulinemia, thereby restoring regular menses, ovulation, and/or fertility.
  • this invention provides a method for treating PCOS comprising coadministering to a patient in need thereof GLP-1, exendin, or agonists or analogs of these compounds with a drug that induces ovulation (e.g., clomiphene, follistim, or Gonal-F).
  • a drug that induces ovulation e.g., clomiphene, follistim, or Gonal-F.
  • this invention provides a method for treating PCOS comprising coadministering to a patient in need thereof GLP-1, exendin, or agonists or analogs of these compounds with an anti-androgenic drug, including but not limited to a birth control pill (e.g., progestogens and estrogens), spironolactone, flutamide and finasteride.
  • an anti-androgenic drug including but not limited to a birth control pill (e.g., progestogens and estrogens), spironolactone, flutamide and finasteride.
  • this invention provides a method for treating PCOS comprising coadministering to a patient in need thereof GLP-1, exendin, or agonists or analogs of these compounds with an insulin-sensitizing agent, including, but not limited to, metformin, D-Chiro-inositol, diazoxide, and PPAR inhibitors (e.g., troglitazone (Rezulin), rosiglitazone (Avandia) and pioglitazone (Actos)).
  • this invention provides a method for treating PCOS comprising coadministering to a patient in need thereof GLP-1, exendin, or agonists or analogs of these compounds with glucose, hi a more preferred embodiment the glucose is administered intravenously.
  • compositions of this invention may be comprised of a combination of a GLP-1, exendin, or agonists or analogs of these compounds molecule and another agent as described above.
  • the subject suffering from PCOS is a mammal, e.g., dog, cat, rodent. In a more preferred embodiment, the subject suffering from PCOS is a human.
  • GLP-1, exendin, and agonists or analogs of these compounds may be formulated into pharmaceutical compositions for administration to subjects, including humans.
  • These pharmaceutical compositions preferably include an amount of GLP-1, exendin, or agonists or analogs of these compounds effective to treat, e.g., insulin resistance, prevent the onset of type-2 diabetes mellitus, restore regular menses and/or ovulation and treat infertility in a subject suffering from PCOS, and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers useful in these pha ⁇ naceutical compositions include, e.g., ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such a s protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers e.g., ion exchangers, alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • compositions of the present invention may be administered parenterally, orally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, infra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered by an infusion pump or subcutaneous injection of a slow release formulation
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art, using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural p harmaceutically-acceptable o ils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents
  • c ommonly u sed i n t he formulation o f p harmaceutically acceptable d osage forms including emulsions and suspensions.
  • Other c ommonly used surfactants such as T weens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • L0 Parenteral formulations may be a single bolus dose, an infusion or a loading bolus dose followed with a maintenance dose. These compositions may be administered once a day or on an "as needed" basis.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and com starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried comstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • compositions of this invention may also be administered topically.
  • Topical application can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
  • Topically transdermal patches may also be used.
  • compositions may be formulated in a
  • Carriers for topical administration of the compounds of this invention include, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in
  • the pharmaceutical compositions may be fonnulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in
  • the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • GLP-1, exendin, or agonists or analogs of these compounds that may be combined with the carrier materials to produce a single dosage form will vary depending on
  • compositions can be formulated so that a dosage of between 0.1-1000 pmoles/kg body weight/minute (when administered by infusion) of GLP-1, exendin, or agonists or analogs of these compounds is administered to a patient receiving these compositions, h some embodiments of the invention, the dosage is 1-10 pmoles/kg body weight/minute (when administered by
  • the dosage is 0.5-2.0 pmoles/kg/min when administered by intravenous infusion.
  • the composition may be administered as a single dose, multiple doses, or over an established period of time in an infusion.
  • GLP-1, exendin, or agonists or analogs of these compounds is administered to patients with confirmed polycystic ovary syndrome.
  • GLP-1, exendin, or agonists or analogs of these compounds is administered by injection at least once a day or by continuous infusion via pump.
  • GLP-1, exendin, or agonists or analogs of these compounds is formulated for administration from a subcutaneous depot over a period of days to weeks, oral administration or by intermittent inhalation.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the particular GLP-1, exendin, or agonists or analogs of these compounds the patient's age, body weight, general health, gender, and diet, and the time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated. Judgment of such factors by medical caregivers is within ordinary skill in the art.
  • the amount of GLP-1, exendin, or agonists or analogs of these c ompounds w ill also depend on the individual patient to be treated, the route of administration, the type of formulation, the characteristics of the compound used, the severity of the disease, and the desired effect.
  • the amounts of GLP-1, exendin, or agonists or analogs of these compounds can be determined by pharmacological and pharmacokinetic principles well-known in the art.
  • PCOS patients with PCOS are exclusively women.
  • premenopausal women manifest the disease with complaints of irregular menses, infertility, excessive growth of body hair, acne and loss of scalp hair.
  • Postmenopausal women may have all of these complaints except irregular menses.
  • Obesity, hypertension and diabetes are disorders that commonly accompany PCOS.
  • PCOS The diagnosis of PCOS will be confirmed by measuring the level of serum testosterone and/or the ratio of serum LH/FSH. Elevated levels of serum testosterone (> 60 ng/ml) or an abnormal serum LH/FSH ratio ( ⁇ 2.5) are indicative of PCOS.
  • GLP-1 will be administered by injection once or more each day or by continuous infusion via pump, which delivers a steady amount of drug.
  • GLP-1 will be formulated for administration from a subcutaneous depot over days to weeks, by intermittent inhalation or orally. Irrespective of the mode of administration, the total amount of GLP-1 delivered into the blood of a patient with PCOS will be in the range of 720 to 2880 picomoles/kg/day. This is equivalent to 0.5-2.0 pmoles/kg/min when administered by intravenous infusion.
  • GLP-1 efficacy will be established by determining the amelioration or reversal of the presenting complaint, including but not limited to normalization of menses, restoration of fertility, loss of excess b ody h air, resolution of acne and cessation of hair loss.
  • Other indicators o f GLP-1 efficacy may b e used including but not limited to serum testosterone levels and LH/FSH ratios.
  • GLP-1 efficacy will be determined by a decrease in serum testosterone levels and an increase in the LH/FSH ratio.

Abstract

La présente invention concerne des méthodes de traitement du syndrome de Stein-Leventhal consistant à administrer de l'exendine ou bien des analogues ou des agonistes de cette substance à des sujets atteints dudit syndrome.
PCT/US2003/023715 2002-12-11 2003-07-30 Methodes et compositions de traitement du syndrome stein-leventhal WO2004052390A1 (fr)

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JP2005508433A JP2006520747A (ja) 2002-12-11 2003-07-30 多嚢胞性卵巣症候群を治療するための方法および組成物
AU2003256988A AU2003256988A1 (en) 2002-12-11 2003-07-30 Methods and compositions for treating polycystic ovary syndrome
EP03812761A EP1581247A4 (fr) 2002-12-11 2003-07-30 Methodes et compositions de traitement du syndrome stein-leventhal

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US10/317,126 2002-12-11
USPCT/US03/01109 2003-01-14
PCT/US2003/001109 WO2003061362A2 (fr) 2002-01-22 2003-01-14 Procedes et compositions pour le traitement du syndrome des ovaires polykystiques

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WO2009040069A2 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
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WO2013079560A1 (fr) 2011-11-29 2013-06-06 Westfälische Wilhelms-Universität Münster Marqueur génétique pour le syndrome des ovaires polykystiques (sopk)
US9198906B2 (en) 2006-10-02 2015-12-01 Cortendo Ab (Publ) Ketoconazole enantiomer in humans
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Cited By (9)

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US20100280046A1 (en) * 2006-01-10 2010-11-04 Diobex, Inc. Methods and Compositions for Treating Prostate Cancer, Benign Prostatic Hypertrophy, Polycystic Ovary Syndrome and Other Conditions
US9198906B2 (en) 2006-10-02 2015-12-01 Cortendo Ab (Publ) Ketoconazole enantiomer in humans
WO2008091177A1 (fr) 2007-01-18 2008-07-31 Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva' Médicament pour le traitement du diabète à base d'exenatide et de dalargine, utilisation et traitement
WO2009040069A2 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009040070A2 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009040069A3 (fr) * 2007-09-11 2009-09-11 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2009040070A3 (fr) * 2007-09-11 2009-09-17 Mondobiotech Laboratories Ag Utilisation d'un peptide en tant qu'agent thérapeutique
WO2013079560A1 (fr) 2011-11-29 2013-06-06 Westfälische Wilhelms-Universität Münster Marqueur génétique pour le syndrome des ovaires polykystiques (sopk)
CN108778285A (zh) * 2015-10-27 2018-11-09 鲁汶大学 与肝脏脂肪变性相关的排卵过少的治疗

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WO2004052390B1 (fr) 2004-09-10
EP1581247A1 (fr) 2005-10-05
EP1581247A4 (fr) 2007-09-12
AU2003256988A1 (en) 2004-06-30
JP2006520747A (ja) 2006-09-14

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