WO1994026292A1 - Antagonistes et agonistes de l'amyline - Google Patents

Antagonistes et agonistes de l'amyline Download PDF

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Publication number
WO1994026292A1
WO1994026292A1 PCT/US1994/005282 US9405282W WO9426292A1 WO 1994026292 A1 WO1994026292 A1 WO 1994026292A1 US 9405282 W US9405282 W US 9405282W WO 9426292 A1 WO9426292 A1 WO 9426292A1
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ala
anb
asn
thr
aib
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PCT/US1994/005282
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Ambikaipakan Balasubramaniam
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University Of Cincinnati
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Priority to EP94917360A priority Critical patent/EP0651651A1/fr
Priority to JP6525694A priority patent/JPH07509008A/ja
Priority to AU69104/94A priority patent/AU669636B2/en
Priority to CA002139651A priority patent/CA2139651A1/fr
Publication of WO1994026292A1 publication Critical patent/WO1994026292A1/fr
Priority to NO950114A priority patent/NO950114L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • 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
    • 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
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to specific amylin analogs which behave as amylin antagonists and agonists, and to their use in the treatment of diabetes mellitus, and hypercalcemia, and the control of food intake.
  • Amylin also known as diabetes associated polypeptide (Cooper et al., Proc. Natl. Acad. Sci. USA. :7763-7766 (1988)) or islet/insulinoma amyloid polypeptide (Westermark et al. , Proc. Natl. Acad. Sci. USA. 84.:3881-3885 (1987)), is a 37-residue polypeptide amide isolated originally from the amyloid-rich pancreas of insulinoma and noninsulin-dependent diabetic (NIDD) patients. It has subsequently been isolated from the normal pancreas of rat (Asai et al., Biochem. Biophys. Res. Commun.
  • NIDD noninsulin-dependent diabetic
  • amylin inhibits basal and insulin-stimulated glucose uptake as well as glycogen synthesis by soleus muscles (Leighton et al., Nature. 335:632-635 (1988)). This peripheral insulin resistance by amylin has also been demonstrated in vivo by euglycemic glucose clamp studies with dogs (Sowa et al., Diabetoloqia. 3_3:118-120 (1990)) and rats (Molina et al., Diabetes. 3_ :260-265 (1990)). Furthermore, these investigations in rats showed that amylin attenuated the inhibition of hepatic glucose output by insulin (Molina et al., supra) .
  • NIDDM noninsulin-dependent diabetes mellitus
  • Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemica, i.e., elevated blood sugar levels. This disease affects a significant percentage of the population.
  • diabetes mellitus There are two major categories of diabetes mellitus, commonly referred to as Type I and Type II.
  • Type I diabetes mellitus In patients with Type I diabetes mellitus, there is a loss of active 3-cells in the islets of Langerhans in the pancreas, resulting in low levels of both insulin and amylin.
  • Cooper Medical Hypothesis. 2(5:284-288 (1991).
  • Patients with Type I diabetes mellitus who are treated with insulin frequently have a tendency to develop hypoglycemia as a side effect.
  • hypoglycemia In patients with Type II diabetes mellitus, there are elevated levels of amylin.
  • amylin like calcitonin, can exhibit serum calcium-lowering effects in rats in vivo as well as in cell culture systems (Datta et al., Biochem. Biophys. Res. Commun.. 162:876-881 (1989)). Amylin has also been shown to act as an anorectic agent. Balasubramaniam et al., Peptides. 12 . :919-924 (1991). Summary of the Invention
  • the invention features amylin analogs which behave as amylin antagonists and agonists.
  • amylin analogs which are linear analogs of biologically active amylin having the following amino acid formula:
  • X is a chain of 0-5 amino acids, inclusive, the N-terminal one of which is bonded to R ⁇ . and R 2 ;
  • Y is a chain of 0-4 amino acids, inclusive, the C-terminal one of which is bonded to Z;
  • R-L, and R 2 independently, is H, C ⁇ - C 12 alkyl (e.g., methyl), C 6 -C 18 aryl (e.g., phenyl, naphthaleneacetyl) , C- ⁇ -C ⁇ acyl (e.g., formyl, acetyl, and myristoyl) , C 7 -C 18 aralkyl (e.g., benzyl), or C 7 -C 18 alkaryl
  • a 8 is Ala, Nal, Thi, Phe, Bth, Pep, N-Me-Thr, Aib, or Anb;
  • a 9 is Thr, Ala, Anb, Aib, Ser, N-Me-Ser, or N-Me-Thr;
  • a 10 is Gin, Ala, Asn, N-Me-Gln, Gly, Nva, Aib, or Anb;
  • a 11 is Arg, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight 5 chain C ⁇ C ⁇ alkyl group, or an aryl group) ,
  • a 12 is Leu, lie, Val, Aib, Anb, or N-Me-Leu;
  • a 13 is Ala, Nal, Thi, Phe, Bth, Pep, N-Me- Thr, Aib, or Anb;
  • ⁇ o A 14 is Asn, Ala, Gin, Gly, N-Me-Asn, Nva,
  • a 15 is Phe, or any aromatic amino acid with or without substituents
  • a 16 is Leu, lie, Val, Aib, Anb, or N-Me-Leu;
  • a 17 is Val, lie, Aib, Anb, or N-Me-Val;
  • a 18 is His, Thr, 3-Me-His, 1-Me-His, ⁇ - pyrozolylalanine, N-Me-His, Arg, homo-Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C ⁇ C ⁇ alkyl 20 group, or an aryl group) , Ala, Aib, Anb, or
  • a 19 is Ser, Thr, N-Me-Ser, N-Me-Thr, Aib, Anb, or Ala;
  • a 20 is Ser, Thr, N-Me-Ser, N-Me-Thr, Aib, 25 Anb, or Ala;
  • a 21 is Asn, Ala, Gin, Gly, N-Me-Asn, Aib, Anb, or Nva;
  • a 22 is Asn, Ala, Gin, Gly, N-Me-Asn, Aib, Anb, or Nva;
  • a 23 is Phe, any aromatic amino acid with or without substituents, Leu, lie, Val, Aib, Anb, Ala, or N-Me-Leu; and
  • Z is NHR 3 or OR 3 ; wherein R 3 is H, C j _-C 12 alkyl, C 7 -C 10 phenylalkyl, C 3 -C 20 alkenyl, C 3 - 35 C 20 alkinyl, phenyl, or naphthyl.
  • the analogs are antagonists.
  • the amylin antagonist corresponds to the N- ⁇ acetyl derivative of amino acids 8 through 23 of human amylin with an amidated carboxy at the C-terminus, referred to herein as N- ⁇ -ac-human amylin (8-23)-NH 2 , having the following formula:
  • amylin antagonist has the following formula:
  • amylin analogs which are linear analogs of biologically active amylin having the following amino acid formula:
  • X is a chain of 0-5 amino acids, inclusive, the N-terminal one of which is bonded to R x and R ;
  • Y is a chain of 0-4 amino acids, inclusive, the C-terminal one of which is bonded to Z;
  • R lf and R 2 independently, is H, C 1 _C 12 alkyl, C 6 -C 18 aryl, Cj-C ⁇ alyl, C 7 -C 18 aralkyl, or C 7 -C 18 alkaryl;
  • a 1 is Lys, Arg, homo-Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C ⁇ -C ⁇ Q alkyl group, or an aryl group) , or Orn;
  • a 2 is Cys, or Anb;
  • a 3 is Asn, Ala, Gin, Gly, N-Me-Asn, Aib, Anb, or Nva;
  • a 4 is Thr, Ser, N-Me-Ser, N-Me-Thr, Ala, Aib, 5 or Anb;
  • a 5 is Ala, Nal, Thi, Phe, Bth, Pep, N-Me-Ala, Aib, or Anb;
  • a 6 is Thr, Ser, N-Me-Ser, N-Me-Thr, Ala, Aib, or Anb; ⁇ o A 7 is Cys, or Anb;
  • a 8 is Ala, Nal, Thi, Phe, Bth, Pep, N-Me-Ala, Aib, or Anb;
  • a 9 is Thr, Ser, N-Me-Ser, N-Me-Thr, Ala, Aib, or Anb;
  • a 10 is Gin, Ala, Asn, N-Me-Gln, Gly, Nva,
  • a 11 is Arg, homo-Arg, diethyl-homo-Arg, Lys- e-NH-R (where R is H, a branched or straight chain C ⁇ C ⁇ alkyl group, or an aryl group) , 20 or Orn;
  • a 12 is Leu, lie, Val, Aib, Anb, or N-Me-Leu;
  • a 13 is Ala, Nal, Thi, Phe, Bth, Pep, N-Me- Ala, Aib, or Anb;
  • a 14 is Asn, Ala, Gin, Gly, N-Me-Asn, Aib, 25 Anb, or Nva;
  • a 15 is Phe, or any aromatic amino acid with or without substituents
  • a 16 is Leu, lie, Val, Aib, Anb, or N-Me-Leu;
  • a 17 is Val, lie, Aib, Anb, or N-Me-Val;
  • 30 A 18 is His, Thr, 3-Me-His, 1-Me-His, ⁇ - pyrozolylalanine, N-Me-His, Arg, homo-Arg, diethyl-homo-Arg, Lys-e-NH-R (where R is H, a branched or straight chain C 1 -C 10 alkyl group, or an aryl group) , Orn, Ala, Aib, or
  • a 19 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Aib, or Anb;
  • a 20 is Ser, Thr, N-Me-Ser, N-Me-Thr, Ala, Aib, or Anb;
  • a 21 is Asn, Ala, Gin, Gly, N-Me-Asn, Aib,
  • a 22 is Asn, Ala, Gin, Gly, N-Me-Asn, Aib, Anb, or Nva;
  • a 23 is Phe, any aromatic amino acid with or without substitutions, Leu, lie, Val, Aib,
  • Z is NHR 3 or OR 3 ; wherein R 3 is H, C 1 -C 12 alkyl, C 7 -C 10 phenylalkyl, C 3 -C 20 alkenyl, C 3 - C 20 alkinyl, phenyl, or naphthyl.
  • the amylin analog corresponds to amino acids 1 through 23 of human amylin with an amidated carboxy at the C-terminus, referred to herein as human amylin (1-23)-NH 2 , having the following formula:
  • amylin analog corresponds to amino acids 1 through 23 of rat amylin, with an amidated carboxy at the C-terminus, referred to herein as rat amylin (1-23)-NH 2 , having the following formula:
  • amylin analog corresponds to the derivative of amino acids 1 through 23 of rat amylin with ⁇ -amino normal butyric acid substitutions at positions 2 and 7, and an amidated carboxy at the C-terminus, referred to herein as [Anb 2 ' 7 ] rat amylin (1-23)-NH 2 , having the following formula:
  • the invention features a method of treating Type II diabetes mellitus in a human being by administering a therapeutic amount of an amylin antagonist of the invention.
  • an amylin antagonist of the invention In a highly preferred method of treatment of Type II diabetes mellitus, N- ⁇ -ac- human amylin (8-23)-NH is adminstered.
  • the invention features a method of treating Type I diabetes mellitus in a human being by administering a therapeutic amount of an amylin agonist of the invention in conjunction with a therapeutic amount of insulin.
  • the invention features a method of treating hypercalcemia by administering a therapeutic amount of an amylin agonist of the invention.
  • the compounds of the invention exhibit a broad range of biological activities, including those related to glucose metabolism, calcium levels in the blood, and appetite.
  • Amylin antagonists of the invention attenuate the inhibition by amylin of insulin-stimulated glucose uptake.
  • the amylin antagonists of the invention act to reduce hyperglycemia resulting from elevated levels of amylin associated with Type II diabetes mellitus.
  • Amylin agonists of the invention inhibit insulin stimulated glucose uptake, thereby tending to increase blood sugar levels.
  • amylin agonists of the invention are useful in reducing the hypoglycemia which frequently accompanies insulin treatment of Type I diabetes mellitus.
  • Amylin agonists of the invention inhibit insulin stimulated glucose uptake, thereby tending to increase blood sugar levels.
  • the amylin agonists of the invention are useful in reducing the hypoglycemia which frequently accompanies insulin treatment of Type I diabetes mellitus.
  • Amylin agonists of the invention also decrease serum calcium levels, and are therefore useful for treating hypercalcemia.
  • amylin agonists exhibit an appetite suppressant effect, while amylin antagonists increase appetite.
  • Amylin agonists and antagonists are therefore useful in controlling food intake. For example, amylin agonists are useful for treating problems of overweight.
  • Fig. 1 shows the comparison of the primary structures of human amylin (hAMYLIN) and rat amylin (rAMYLIN) .
  • Fig. 2 shows the effect of human amylin, and N- ⁇ - ac-human amylin (8-23)-NH 2 , separately and together, on glucose uptake in C 2 C 1 muscle cells.
  • Fig. 3a and Fig. 3b show the in vivo effects of saline, rat amylin, N- ⁇ -ac-human amylin (8-23)-NH 2 , and N- ⁇ -ac-human amylin (8-23)-NH 2 plus rat amylin on plasma glucose levels, and plasma insulin levels, respectively, in Sprague Dawley rats.
  • Fig. 4 shows the in vitro effect of human amylin and human amylin (1-23)-NH 2 , separately, on insulin stimulated glucose uptake in C 2 C 12 muscle cells.
  • Fig. 5a and 5b show the in vivo effects of saline, rat amylin, human amylin (1-23)-NH 2 , and human amylin (1- 23)-NH 2 plus rat amylin on plasma glucose levels, and plasma insulin levels, respectively, in Sprague Dawley rats.
  • Fig. 6 shows the in vitro effects of rat amylin (1-23)-NH 2 and [Anb 2 ' 7 ] rat amylin (1-23)-NH 2 , separately, on insulin stimulated glucose uptake in C 2 C 12 muscle cells.
  • Fig. 7a and 7b show the in vivo effects of saline, rat amylin, [Anb 2 ' 7 ] rat amylin (1-23)-NH 2 , and [Anb 2 ' 7 ] rat amylin (1-23)-NH 2 plus rat amylin on plasma glucose levels, and plasma insulin levels, respectively, in Sprague Dawley rats.
  • amylin analogs of the invention are based upon the biologically active subfragments comprising amino acids 8-23 of hAmylin and rAmylin and derivatives thereof; and upon the biologically active subfragments comprising amino acids 1-23 of hAmylin and rAmylin and derivatives thereof.
  • the symbols A x and the like; and Ser, Leu and the like, as found in a peptide sequence herein stand for amino acid residues.
  • an amino acid residue is optically active, it is the L-form configuration that is intended unless the D-form is expressly designated.
  • Ornithine Nal 2-napthylalanine
  • Nva norvaline
  • Thi 2-thienylalanine
  • Pep 4-chlorophenylalanine
  • Bth 3-benzothienyalanine
  • Bip 4,4'-biphenylalanine
  • Tic tetrahydroisoquinoline-3-carboxylic acid
  • Aib aminoisobutyric acid
  • Anb ⁇ -aminonormalbutyric acid
  • Dip 2,2-diphenylalanine
  • the compounds of the present invention can be provided in the form of pharmaceutically acceptable salts.
  • Examples of preferred salts are those with therapeutically acceptable organic acids, e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methane sulfonic, toluene sulfonic, trifluoroacetic, or pamoic acid, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids, such as the hydrohalic acids, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid and the like.
  • organic acids e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methane sulfonic, toluene sulfonic, trifluoroacetic, or pamoic acid
  • polymeric acids such as tannic acid or carboxymethyl cellulose
  • salts with inorganic acids such as the hydrohalic
  • amylin and amylin analogs were studied both in an in vitro model using a mouse muscle cell line, C 2 C 12 , and an in vivo model using Sprague Dawley rats.
  • insulin stimulated the glucose uptake by the C C 12 cell line in a dose-dependent manner and this was attenuated by rat amylin (100 pM) .
  • rat amylin did not exhibit any effect on the basal glucose uptake by this cell line.
  • Cholera toxin did not have any effect on insulin stimulated glucose uptake but blocked the inhibitory effect of rat amylin.
  • Peptide synthesis was accomplished on an Applied Biosystem Model 430A synthesizer.
  • HPLC was carried out on a Waters Model 600 solvent delivery system in conjunction with a U6K injector.
  • Protected amino acid derivatives (Peninsula, CA) , synthesis reagents (Applied Biosystems, CA) and solvents (Fischer Scientific, OH) were obtained commercially and used without further purification.
  • Paramethylbenzhydroxylamine (MBHA) resin (0.45 mmol, NH 2 group) was placed in the reaction vessel of the synthesizer and the amino acid derivatives were coupled automatically using the standard program provided by the manufacturers modified to incorporate a double coupling procedure.
  • C 2 C 12 cells were cultured at 37°C in a humidified 5% C0 2 atmosphere, in low glucose (1 g/1) DMEM medium containing 20% fetal bovine serum, and 0.5% chick embryo extract (growth medium) .
  • Cells were seeded in 75-cm 2 flasks at a density of lxlO 6 cells per flask. When the cells became confluent (3-4 days) , they were trypsinized (0.25% trypsin) and washed with growth medium. The final cell pellet was suspended in growth medium and seeded at a density of 2.5-10 4 cells/well into 24 well plates (16 mm diameter) and allowed to grow to 70% confluence (3 days) .
  • the mononucleated myoblasts were exposed to medium containing 10% horse serum instead of 20% FBS (fusion medium) . Fusion media was changed every day to avoid the premature detachment of cells and the cells were almost completely fused into multinucleated myotubes by the 9th day (6 days in fusion medium) . Medium was changed one day before the experiment.
  • FBS fusion medium
  • Non-carrier-mediated uptake was determined by incubating the cells with cytochalasin B (15 j- ⁇ M) . Uptake was terminated by rapidly aspirating the solution, and cells were washed with ice-cold PBS. Cell-associated radioactivity was determined by lysing the cells in 1 M NaOH and the aliquots were neutralized and counted in a scintillation counter. Protein content of the aliquots was determined by the Lowry method.
  • Sprague Dawley rats (Zivic Miller, Zelienople, PA) used in this investigation were housed individually in air-conditioned rooms (22-24°C) under 12-hour light/dark cycle with ad lib access to Purina rat chow and water.
  • Sprague Dawley rats weighing about 300g were fasted overnight (18-22 hrs) .
  • Rats were then anesthetized with sodium pentobarbital (40 mg/kg) and catheters were implanted in the jugular vein.
  • Plasma glucose and insulin levels were determined by the glucose oxidase method (Model 27 glucose analyzer, Yellow Springs Instruments, Yellow Springs, OH) and a radioimmunoassay kit (Peninsula Laboratories, Bel ont, CA) , respectively.
  • N- ⁇ -ac-human amylin(8-23)-NH 2 exhibited no significant effect on insulin stimulated glucose uptake in the in vitro assay when tested separately. Still referring to Fig. 2, the presence of N- ⁇ -ac-human amylin (8-23)-NH 2 (l ⁇ M) with human amylin consistently shifted the inhibitory dose-response curve of human amylin on insulin stimulated glucose uptake to the right (i.e.. higher concentrations of human amylin) , increasing the IC 50 value from 0.20 nM to 350 nM.
  • N- ⁇ -ac-human amylin (8-23)-NH were investigated in anesthetized (45 mg/kg) Sprague Dawley rats ( ⁇ 300 g) fasted overnight (> 20 h) .
  • rat amylin significantly increased the plasma glucose level compared to the saline control
  • N- ⁇ -ac-human amylin (8-23)-NH 2 significantly decreased the plasma glucose levels relative to the control, probably by antagonizing the effects of endogenous amylin.
  • Fig. 3a rat amylin significantly increased the plasma glucose level compared to the saline control
  • N- ⁇ -ac-human amylin (8-23)-NH 2 significantly decreased the plasma glucose levels relative to the control, probably by antagonizing the effects of endogenous amylin.
  • N- ⁇ -ac-human amylin (8-23)-NH 2 significantly attenuated the elevation of plasma glucose by rat amylin in the rat which received both N- ⁇ -ac-human amylin (8- 23)-NH 2 and rat amylin (i.e. plasma glucose levels were brought down near the control value) .
  • the p values in Fig. 3a and 3b, and throughout, refer to values obtained using the ANOVA program with n equal to 5 to 8.
  • N- ⁇ -ac-human amylin (8-23)-NH 2 is a potent antagonist of human amylin in vitro, and of rat amylin in vivo.
  • human amylin (l-23)-NH 2 inhibited insulin stimulated glucose uptake in the in vitro assay in a manner similar to human amylin. Still referring to Fig. 4, human amylin (1-23)-NH 2 exhibited a dose-response inhibitory effect on insulin-stimulated glucose uptake by C 2 C 12 cells with a potency comparable to that of intact human amylin.
  • human amylin (1-23)-NH 2 attenuated rat amylin induced hyperglycemia.
  • rat amylin(1-23)-NH 2 inhibited the insulin stimulated glucose uptake in the in vitro assay in a manner qualitatively similar to rat amyli (1-23)-NH 2 .
  • rat amylin (1-23)-NH 2 exhibited a dose-response inhibitory effect on insulin-stimulated glucose uptake by C 2 C 12 cells with a potency comparable to that of intact human amylin.
  • [Anb 2 ' 7 ] rat amylin (1-23)-NH 2 also exhibited a potency comparable to that of human amylin.
  • rat amylin inhibits 5 elevates ⁇ lowered*
  • RA(l-23)-NH 2 inhibits (similar to N.D. N.D. NJ human amylin) (Fig. 6) o
  • the agonist or antagonist effect of other amylin analogs of the invention may be determined by the assays described above.
  • Amylin inhibits insulin stimulated glucose uptake and glycogen synthesis, and increases the hepatic glucose output. Therefore, it appears that a particular ratio of insulin to amylin is required to maintain the normal plasma glucose levels.
  • amylin agonists and antagonists of the invention have useful applications in treating Type I and II diabetes mellitus, respectively. Since humans with Type II diabetis mellitus have elevated levels of amylin and elevated blood glucose levels, administration of an amylin antagonist of the invention in an amount sufficient to decrease blood glucose levels to normal or clinically acceptable levels provides therapeutic results. Humans with Type I diabetis mellitus have decreased levels of both insulin and amylin, and when treated with insulin have a tendency to develop hypoglycemia. Administration of an amylin agonist of the invention in an amount sufficient to increase blood glucose levels to normal or clinically acceptable levels in response to insulin induced hypoglycemia, together with a therapeutic amount of insulin, provides therapeutic results.
  • Amylin agonists of the invention decrease serum calcuim levels and may be administered to humans to treat hypercalcemi .
  • Amylin agonists of the invention exhibit an appetite suppressant effect, while amylin antagonists increase appetite.
  • Amylin agonists and antagonists of the invention are therefore useful in controlling food intake.
  • amylin agonists of the invention may be administered for the treatment of obesity.
  • the peptides of the invention may be administered to a human in one of the traditional modes (e.g., orally, parenterally, transdermally, or transmucosally) , or in a sustained release formulation using a biodegradable biocompatible polymer.
  • GENERAL INFORMATION (i) APPLICANT: A. Balasubramaniam (ii) TITLE OF INVENTION: AMYLIN ANTAGONISTS AND AGONISTS (iii) NUMBER OF SEQUENCES: 7 (iv) CORRESPONDENCE ADDRESS:

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Abstract

L'invention concerne des analogues de l'amyline qui se comportent comme des antagonistes et des agonistes de l'amyline. L'invention concerne également l'utilisation de l'antagoniste de l'amyline dans le traitement du diabète sucré du type II, et l'utilisation des agonistes de l'amyline dans le traitement à la fois du diabète sucré du type I et de l'hypercalcémie. L'invention concerne également l'utilisation des antagonistes et des agonistes de l'amyline dans la régulation de l'apport alimentaire.
PCT/US1994/005282 1993-05-12 1994-05-11 Antagonistes et agonistes de l'amyline WO1994026292A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP94917360A EP0651651A1 (fr) 1993-05-12 1994-05-11 Antagonistes et agonistes de l'amyline
JP6525694A JPH07509008A (ja) 1993-05-12 1994-05-11 アミリン・アンタゴニストおよびアゴニスト
AU69104/94A AU669636B2 (en) 1993-05-12 1994-05-11 Amylin antagonists and agonists
CA002139651A CA2139651A1 (fr) 1993-05-12 1994-05-11 Antagonistes et agonistes de l'amyline
NO950114A NO950114L (no) 1993-05-12 1995-01-11 Amylin-antagonister og agonister

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US6026593A 1993-05-12 1993-05-12
US08/060,265 1993-05-12

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US5739106A (en) * 1995-06-07 1998-04-14 Rink; Timothy J. Appetite regulating compositions
WO2000011029A2 (fr) * 1998-08-21 2000-03-02 Amylin Pharmaceuticals, Inc. Nouveaux peptides antidiabetiques
US7910548B2 (en) * 1997-06-06 2011-03-22 Amylin Pharmaceuticals, Inc. Methods for treating obesity
US8114958B2 (en) 2004-02-11 2012-02-14 Amylin Pharmaceuticals, Inc. Amylin family peptides
US8575091B1 (en) 2012-04-19 2013-11-05 Novo Nordisk A/S Amylin analogues and pharmaceutical compositions thereof

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US5266561A (en) * 1988-01-11 1993-11-30 Amylin Pharmaceuticals, Inc. Treatment of type 2 diabetes mellitus

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US5580953A (en) * 1991-08-14 1996-12-03 Amylin Pharmaceuticals, Inc. Amylin antagonist peptides and uses therefor

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Biochemical and Biophysical Research Communications, Vol. 160, No. 2, issued 28 April 1989, OHSAWA et al., "Islet Amyloid Polypeptide Inhibits Glucose-Stimulated Insulin Secretion from Isolated Rat Pancreatic Islets", pages 961-967, see entire document. *
Proceedings of the National Academy of Science USA, Vol. 84, issued June 1987, WESTERMARK et al., "Amyloid Fibrils in Human Insulinoma and Islets of Langerhans of the Diabetic Cat are Derived from a Neuropeptid-Like Protein also Present in Normal Islet Cells", pages 3881-3885, see entire document. *
Proceedings of the National Academy of Science USA, Vol. 85, issued 1988, COOPER et al., "Amylin Found in Amyloid Deposits in Human Type 2 Diabetes Mellitus may be Hormone that Regulates Glycogen Metabolism in Skeletal Muscle", pages 7763-7766, see entire document. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5739106A (en) * 1995-06-07 1998-04-14 Rink; Timothy J. Appetite regulating compositions
US7910548B2 (en) * 1997-06-06 2011-03-22 Amylin Pharmaceuticals, Inc. Methods for treating obesity
WO2000011029A2 (fr) * 1998-08-21 2000-03-02 Amylin Pharmaceuticals, Inc. Nouveaux peptides antidiabetiques
WO2000011029A3 (fr) * 1998-08-21 2000-06-22 Amylin Pharmaceuticals Inc Nouveaux peptides antidiabetiques
US8114958B2 (en) 2004-02-11 2012-02-14 Amylin Pharmaceuticals, Inc. Amylin family peptides
US8598120B2 (en) 2004-02-11 2013-12-03 Amylin Pharmaceuticals, Llc Methods for treatment using amylin family peptides
US8575091B1 (en) 2012-04-19 2013-11-05 Novo Nordisk A/S Amylin analogues and pharmaceutical compositions thereof
US9023789B2 (en) 2012-04-19 2015-05-05 Novo Nordisk A/S Amylin analogs and pharmaceutical compositions thereof

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JPH07509008A (ja) 1995-10-05
HUT70176A (en) 1995-09-28
ZA943251B (en) 1995-01-16
CZ5795A3 (en) 1995-11-15
RU95106486A (ru) 1996-12-27
AU669636B2 (en) 1996-06-13
CA2139651A1 (fr) 1994-11-24
EP0651651A1 (fr) 1995-05-10
AU6910494A (en) 1994-12-12
PL307138A1 (en) 1995-05-02

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