WO1998055139A1 - Use of leptin antagonists for the treatment of diabetes - Google Patents

Use of leptin antagonists for the treatment of diabetes Download PDF

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Publication number
WO1998055139A1
WO1998055139A1 PCT/EP1997/002240 EP9702240W WO9855139A1 WO 1998055139 A1 WO1998055139 A1 WO 1998055139A1 EP 9702240 W EP9702240 W EP 9702240W WO 9855139 A1 WO9855139 A1 WO 9855139A1
Authority
WO
WIPO (PCT)
Prior art keywords
leptin
treatment
insulin
mice
antagonist
Prior art date
Application number
PCT/EP1997/002240
Other languages
English (en)
French (fr)
Inventor
Michael Anthony Cawthorne
Valur Emilsson
Yong-Ling Liu
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU29517/97A priority Critical patent/AU2951797A/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to CA002293504A priority patent/CA2293504A1/en
Priority to HU0003428A priority patent/HUP0003428A3/hu
Priority to PL97337220A priority patent/PL337220A1/xx
Priority to JP50135299A priority patent/JP2002504102A/ja
Priority to IL13313697A priority patent/IL133136A0/xx
Priority to KR19997011415A priority patent/KR20010013414A/ko
Priority to BR9714726A priority patent/BR9714726A/pt
Priority to TR1999/02980T priority patent/TR199902980T2/xx
Priority to PCT/EP1997/002240 priority patent/WO1998055139A1/en
Priority to EP97923840A priority patent/EP0986397A1/en
Publication of WO1998055139A1 publication Critical patent/WO1998055139A1/en
Priority to NO995940A priority patent/NO995940L/no

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/2264Obesity-gene products, e.g. leptin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention relates to a novel use, in particular a use for the treatment of diabetes and complications thereof.
  • NIDDM non-insulin-dependent diabetes
  • IIDDM insulin resistance
  • an inadequate insulin secretion from the beta-cells of the Islets of Langerhans in the pancreas Thus, despite hyperinsulinaemia there is insufficient insulin to compensate for the insulin resistance and to maintain blood glucose in the desirable range.
  • Pelleymounter et al (Science, 1995, 269, 540-543) have reported that the ob polypeptide or "leptin” lowers both plasma insulin and glucose levels in the genetically obese ob/ob mouse.
  • United Kingdom patent application, Publication Number 2292382 relates ter alia to polypeptides, OB polypeptides, and antagonists thereof and their use for modulating body weight.
  • the disclosures of GB 2292382 are incorporated herein by reference.
  • leptin directly inhibits insulin release from both isolated islets and the perfused pancreas of the ob/ob mouse.
  • An antagonist of leptin is therefore indicated to be of value in enhancing insulin secretion and thereby assisting in the control of blood glucose levels.
  • leptin inhibits basal and insulin-stimulated glycogen synthesis in isolated soleus muscle of ob/ob mice.
  • An antagonist of leptin is therefore also indicated to be of value in enhancing glucose utilisation and the action of insulin to enhance glucose utilisation.
  • Antagonists are therefore indicated to be of direct use in the treatment of disorders resulting from deficiencies in insulin secretion and action and of hyperglycaemia, such as non-insulin- dependent diabetes.
  • an antagonist which enhances insulin secretion and assists in blood glucose control may be useful in the treatment of diabetic complications, such as retinopathy, nephropathy and angiopathy.
  • the invention provides the use of an antagonist of leptin for the treatment of disorders resulting from deficiencies in insulin secretion and of hyperglycaemia, such as non-insulin-dependent diabetes (NIDDM).
  • NIDDM non-insulin-dependent diabetes
  • NIDDM non-insulin-dependent diabetes
  • Suitable antagonists of leptin are as disclosed in GB2292382 and may be prepared according to methods disclosed therein.
  • Particular antagonists include protein antagonists.
  • Particular antagonists include non-protein antagonists, especially small organic molecule antagonists.
  • the present invention also extends to a method for the treatment of disorders resulting from deficiencies in insulin secretion and of hyperglycaemia, such as non- insulin-dependent diabetes (NIDDM), in a human or non-human mammal, which method comprises the administration to human or non-human mammal in need of such treatment, an effective, pharmaceutically acceptable, non-toxic amount of an antagonist of leptin.
  • NIDDM non- insulin-dependent diabetes
  • the present invention also extends to a pharmaceutical composition
  • a pharmaceutical composition comprising an antagonist of leptin, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier.
  • Particular compositions of the invention are those used for the treatment of disorders resulting from deficiencies in insulin secretion and of hyperglycaemia, such as non-insulin-dependent diabetes (NIDDM).
  • NIDDM non-insulin-dependent diabetes
  • Suitable pharmaceutically acceptable carriers are as dictated by conventional practice such as those disclosed in GB 2292382 or in International Patent Application, Publication Number WO 94/01420.
  • compositions of the invention are prepared according to conventional practice, such as described in the above mentioned patent applications
  • the dosages of the antagonists may be determined according to conventional methodology such as those described in the above mentioned patent applications.
  • the following is a brief description of the figures ( Figures 1-5 and Table 1) of the application:
  • Figure 1 and Table 1 show the effect of leptin (lOOnM) on basal insulin secretion from the perfused pancreas of ob mice;
  • Figure 2 shows the effect of leptin (100 nmol/1) on glucose stimulated (16.7 mmol/1) insulin secretion from ob/ob islets;
  • Figure 3 shows the dose - dependency of inhibitory effects of recombinant leptin on glucose-stimulated (16.7 mmol/1) insulin secretion from isolated pancreatic islets of ob/ob mice;
  • Figure 4 shows the effect of leptin on glycogen synthesis in isolated soleus muscle of ob/ob mice.
  • Figure 5 shows the effect of leptin on the glycogen synthesis in isolated soleus muscle of ob/ob mice.
  • an especially useful antagonist would be one that antagonizes the action of leptin at the islet and/or skeletal muscle receptor, but does not antagonize other leptin receptors (e.g. in the hypothalamus) and thereby exacerbate insulin resistance.
  • the leptin receptor has several alternatively spliced variants.
  • One of these spliced variants is expressed at a high level in hypothalamus, and is believed to be the functional receptor in the regulation of energy balance. It is abnormally spliced in C57B1/KSJ db/db mice (Nature (Lond.) 379, 622-635 (1996); Cell
  • leptin has both central and peripheral actions.
  • the diabetic (db) gene product in mice has been identified as the receptor for leptin. At least six alternatively spliced forms of the leptin message have been identified
  • Ob-Rb has an extensive intracellular region containing a Box 2 sequence motif, which is required for the binding of JAK protein kinases and is believed to encode the functional receptor.
  • Short antisense oligodeoxynucleotide probes (Trayhurn et al, Biochem. Soc. Trans. Vol 23 page 4945, 1995) 30-34 mers, were designed to hybridise with different domains in the mouse leptin
  • oligonucleotide probe sequence was unique to the leptin receptor and had no significant homology to any other known sequence.
  • Total leptin receptor mRNA, standardised to poly(A) mRNA levels was over-expressed in ob/ob mice relative to the lean littermates. However, there were tissue specific differences in overexpression. Thus, hypothalamus which shows the highest level of expression in lean mice was only 2-fold
  • this leptin receptor Ob-Rb gave a single sharp band. This contrasted with the multiple bands when the blot was probed with the 33-mer corresponding to bases 1877-1910, which is a sequence common to all the known splice variants of the leptin receptor. Molecular weight markers indicated that the 34-mer hybridised to a mRNA fragment of approximately 3400 b.p. consistent with the putative functional leptin receptor. This was
  • Leptin (lOOnM) produced an immediate reduction in the insulin release from the isolated pancreas.
  • leptin in the perfused pancreas preparation could be either direct on
  • leptin islets or via the release of a further mediator from the vasculature.
  • leptin completely inhibited the stimulatory effect of 16.7mM glucose on insulin release in islets isolated from overnight-fasted mice (Fig.2).
  • the inhibitory effect of leptin was dose-related over the range 1-lOOnM (Fig. 3). Also leptin
  • Obesity is the commonest nutritional disorder in Western Society and in many
  • leptin overproduction associated with obesity may be one
  • the present invention provides the use of an antagonist of leptin for the treatment of insulin resistance, especially that associated with obesity.
  • a method for the treatment of of insulin resistance, especially that associated with obesity, in a human or non-human mammal comprises the administration to human or non-human mammal in need of such treatment, an effective, pharmaceutically acceptable, non-toxic amount of an antagonist of leptin.
  • a further particular pharmaceutical composition of the invention is therefore a pharmaceutical composition useful for the treatment of of insulin resistance, especially that associated with obesity.
  • pancreatic islets we have also detected the long-form of the leptin receptor in liver, kidney and lung. The functional effects of leptin in these tissues are at 210 present unknown.
  • Levin et_al Proc. Natl, Acad. ScL, USA 93, 1726-1730

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Obesity (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/EP1997/002240 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes WO1998055139A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
IL13313697A IL133136A0 (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes
CA002293504A CA2293504A1 (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes
HU0003428A HUP0003428A3 (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes
PL97337220A PL337220A1 (en) 1997-06-06 1997-06-06 Application of leptin antagonists in treating diabetes
JP50135299A JP2002504102A (ja) 1997-06-06 1997-06-06 糖尿病治療のためのレプチン拮抗物質の使用
AU29517/97A AU2951797A (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes
KR19997011415A KR20010013414A (ko) 1997-06-06 1997-06-06 당뇨병의 치료를 위한 렙틴 길항제의 용도
PCT/EP1997/002240 WO1998055139A1 (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes
TR1999/02980T TR199902980T2 (xx) 1997-06-06 1997-06-06 Diabetin tedavisi i�in leptin antagonistlerinin kullan�m�.
BR9714726A BR9714726A (pt) 1997-06-06 1997-06-06 Uso de antagonistas da leptina no tratamento de diabete
EP97923840A EP0986397A1 (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabet
NO995940A NO995940L (no) 1997-06-06 1999-12-03 Anvendelse av leptin antagonister for behandling av diabetes

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP1997/002240 WO1998055139A1 (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US09445524 A-371-Of-International 2000-03-24
US09/922,675 Continuation US20020002181A1 (en) 1996-04-26 2001-08-06 Use of leptin antagonists for the treatment of diabetes
US10/133,285 Continuation US20020160935A1 (en) 1996-04-26 2002-04-26 Use of leptin antagonists for the treatment of diabetes

Publications (1)

Publication Number Publication Date
WO1998055139A1 true WO1998055139A1 (en) 1998-12-10

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/002240 WO1998055139A1 (en) 1997-06-06 1997-06-06 Use of leptin antagonists for the treatment of diabetes

Country Status (9)

Country Link
EP (1) EP0986397A1 (ja)
JP (1) JP2002504102A (ja)
KR (1) KR20010013414A (ja)
AU (1) AU2951797A (ja)
CA (1) CA2293504A1 (ja)
HU (1) HUP0003428A3 (ja)
IL (1) IL133136A0 (ja)
TR (1) TR199902980T2 (ja)
WO (1) WO1998055139A1 (ja)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7786265B2 (en) 1998-08-21 2010-08-31 Albany Medical College Isolated antibodies against biologically active leptin-related peptides
US7790683B2 (en) 1998-08-21 2010-09-07 Albany Medical College Leptin-related peptides
WO2010118384A2 (en) 2009-04-10 2010-10-14 Amylin Pharmaceuticals, Inc. Amylin agonist compounds for estrogen-deficient mammals
US7875587B2 (en) 1999-03-29 2011-01-25 Uutech Limited Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
EP2330125A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals, Inc. Hybrid polypeptides with selectable properties
EP2330124A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
EP2390264A1 (en) 2005-02-11 2011-11-30 Amylin Pharmaceuticals Inc. GIP analog and hybrid polypeptides with selectable propperties
US8076288B2 (en) 2004-02-11 2011-12-13 Amylin Pharmaceuticals, Inc. Hybrid polypeptides having glucose lowering activity
EP2417980A1 (en) 2004-02-11 2012-02-15 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
WO2012050925A2 (en) 2010-09-28 2012-04-19 Amylin Pharmaceuticals, Inc. Highly soluble leptins
US8263545B2 (en) 2005-02-11 2012-09-11 Amylin Pharmaceuticals, Inc. GIP analog and hybrid polypeptides with selectable properties
WO2013009539A1 (en) 2011-07-08 2013-01-17 Amylin Pharmaceuticals, Inc. Engineered polypeptides having enhanced duration of action and reduced immunogenicity
US8497240B2 (en) 2006-08-17 2013-07-30 Amylin Pharmaceuticals, Llc DPP-IV resistant GIP hybrid polypeptides with selectable properties
WO2014052583A1 (en) 2012-09-27 2014-04-03 The Children's Medical Center Corporation Compounds for the treatment of obesity and methods of use thereof
WO2015081093A1 (en) 2013-11-26 2015-06-04 The Chilren's Medical Center Corporation Compounds for the treatment of obesity and methods of use thereof
WO2015153933A1 (en) 2014-04-03 2015-10-08 The Children's Medical Center Corporation Hsp90 inhibitors for the treatment of obesity and methods of use thereof
WO2018049424A1 (en) 2016-09-12 2018-03-15 Aegerion Pharmaceuticals, Inc. Methods of detecting anti-leptin neutralizing antibodies

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2292382A (en) * 1994-08-17 1996-02-21 Univ Rockefeller Obesity(OB) polypeptides
WO1997002004A2 (en) * 1995-06-30 1997-01-23 Eli Lilly And Company Methods for treating diabetes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2292382A (en) * 1994-08-17 1996-02-21 Univ Rockefeller Obesity(OB) polypeptides
WO1997002004A2 (en) * 1995-06-30 1997-01-23 Eli Lilly And Company Methods for treating diabetes

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HOUSEKNECHT K L ET AL: "EVIDENCE FOR LEPTIN BINDING TO PROTEINS IN SERUM OF RODENTS AND HUMANS: MODULATION WITH OBESITY", DIABETES, vol. 45, no. 11, November 1996 (1996-11-01), pages 1638 - 1643, XP002047308 *
PELLEYMOUNTER M A ET AL: "EFFECTS OF THE OBESE GENE PRODUCT ON BODY WEIGHT REGULATION IN OB/OB MICE", SCIENCE, vol. 269, no. 5223, 28 July 1995 (1995-07-28), pages 540 - 543, XP000602063 *
ROHNER-JEANRENAUD F ET AL: "Central nervous system and body weight regulation.", ANNALES D'ENDOCRINOLOGIE 58 (2). 1997. 137-142, XP002054626 *
TAYLOR S I ET AL: "Does leptin contribute to diabetes caused by obesity? [comment].", SCIENCE, vol. 274, no. 5290, 15 November 1996 (1996-11-15), pages 1151 - 1152, XP002054625 *

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7790683B2 (en) 1998-08-21 2010-09-07 Albany Medical College Leptin-related peptides
US7786265B2 (en) 1998-08-21 2010-08-31 Albany Medical College Isolated antibodies against biologically active leptin-related peptides
US8022189B2 (en) 1998-08-21 2011-09-20 Albany Medical College Isolated antibodies against biologically active leptin-related peptides
US8067545B2 (en) 1998-08-21 2011-11-29 Albany Medical College Isolated antibodies against biologically active leptin-related peptides
US7875587B2 (en) 1999-03-29 2011-01-25 Uutech Limited Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
EP2417980A1 (en) 2004-02-11 2012-02-15 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
US9453063B2 (en) 2004-02-11 2016-09-27 Amylin Pharmaceuticals, Llc. Hybrid polypeptides with selectable properties
EP2422806A2 (en) 2004-02-11 2012-02-29 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
US8697647B2 (en) 2004-02-11 2014-04-15 Odile Esther Levy Hybrid polypeptides with selectable properties
EP2422807A2 (en) 2004-02-11 2012-02-29 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
US8076288B2 (en) 2004-02-11 2011-12-13 Amylin Pharmaceuticals, Inc. Hybrid polypeptides having glucose lowering activity
EP2390264A1 (en) 2005-02-11 2011-11-30 Amylin Pharmaceuticals Inc. GIP analog and hybrid polypeptides with selectable propperties
EP2392595A1 (en) 2005-02-11 2011-12-07 Amylin Pharmaceuticals Inc. GIP analog and hybrid polypeptides with selectable properties
US9133260B2 (en) 2005-02-11 2015-09-15 Amylin Pharmaceuticals, Llc GIP analog and hybrid polypeptides with selectable properties
US8263545B2 (en) 2005-02-11 2012-09-11 Amylin Pharmaceuticals, Inc. GIP analog and hybrid polypeptides with selectable properties
US8895498B2 (en) 2005-02-11 2014-11-25 Astrazeneca Pharmaceuticals, Lp GIP and exendin hybrid polypeptides
US8404637B2 (en) 2005-02-11 2013-03-26 Amylin Pharmaceuticals, Llc GIP analog and hybrid polypeptides with selectable properties
EP2330124A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals Inc. Hybrid polypeptides with selectable properties
EP2330125A2 (en) 2005-08-11 2011-06-08 Amylin Pharmaceuticals, Inc. Hybrid polypeptides with selectable properties
US8497240B2 (en) 2006-08-17 2013-07-30 Amylin Pharmaceuticals, Llc DPP-IV resistant GIP hybrid polypeptides with selectable properties
WO2010118384A2 (en) 2009-04-10 2010-10-14 Amylin Pharmaceuticals, Inc. Amylin agonist compounds for estrogen-deficient mammals
WO2012050925A2 (en) 2010-09-28 2012-04-19 Amylin Pharmaceuticals, Inc. Highly soluble leptins
EP3241558A2 (en) 2010-09-28 2017-11-08 Aegerion Pharmaceuticals, Inc. Highly soluble leptins
US11535659B2 (en) 2010-09-28 2022-12-27 Amryt Pharmaceuticals Inc. Engineered polypeptides having enhanced duration of action
EP3305315A1 (en) 2010-09-28 2018-04-11 Aegerion Pharmaceuticals, Inc. Engineered polypeptides having enhanced duration of action
US10087228B2 (en) 2010-09-28 2018-10-02 Aegerion Pharmaceuticals, Inc. Chimeric leptin polypeptide and method of using the same
WO2013009539A1 (en) 2011-07-08 2013-01-17 Amylin Pharmaceuticals, Inc. Engineered polypeptides having enhanced duration of action and reduced immunogenicity
US9879063B2 (en) 2011-07-08 2018-01-30 Aegerion Pharmaceuticals, Inc. Engineered polypeptides having enhanced duration of action and reduced immunogenicity
EP4082541A1 (en) 2012-09-27 2022-11-02 The Children's Medical Center Corporation Compounds for the treatment of obesity and methods of use thereof
WO2014052583A1 (en) 2012-09-27 2014-04-03 The Children's Medical Center Corporation Compounds for the treatment of obesity and methods of use thereof
WO2015081093A1 (en) 2013-11-26 2015-06-04 The Chilren's Medical Center Corporation Compounds for the treatment of obesity and methods of use thereof
WO2015153933A1 (en) 2014-04-03 2015-10-08 The Children's Medical Center Corporation Hsp90 inhibitors for the treatment of obesity and methods of use thereof
US10775386B2 (en) 2016-09-12 2020-09-15 Aegerion Pharmaceuticals, Inc. Methods of detecting anti-leptin neutralizing antibodies
WO2018049424A1 (en) 2016-09-12 2018-03-15 Aegerion Pharmaceuticals, Inc. Methods of detecting anti-leptin neutralizing antibodies
US11709166B2 (en) 2016-09-12 2023-07-25 Amryt Pharmaceuticals Inc. Methods of detecting anti-leptin neutralizing antibodies
EP4283304A2 (en) 2016-09-12 2023-11-29 Amryt Pharmaceuticals Inc. Methods of detecting anti-leptin neutralizing antibodies

Also Published As

Publication number Publication date
EP0986397A1 (en) 2000-03-22
AU2951797A (en) 1998-12-21
KR20010013414A (ko) 2001-02-26
JP2002504102A (ja) 2002-02-05
HUP0003428A2 (hu) 2001-05-28
IL133136A0 (en) 2001-03-19
CA2293504A1 (en) 1998-12-10
TR199902980T2 (xx) 2000-05-22
HUP0003428A3 (en) 2001-12-28

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