WO1998024464A1 - Antagonistes specifiques du polypeptide glucodependant insulinotrope (gip) - Google Patents

Antagonistes specifiques du polypeptide glucodependant insulinotrope (gip) Download PDF

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Publication number
WO1998024464A1
WO1998024464A1 PCT/US1997/022418 US9722418W WO9824464A1 WO 1998024464 A1 WO1998024464 A1 WO 1998024464A1 US 9722418 W US9722418 W US 9722418W WO 9824464 A1 WO9824464 A1 WO 9824464A1
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gip
antagonist
glucose
sequence
glp
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PCT/US1997/022418
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English (en)
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Michael M. Wolfe
Chi-Chuan Tseng
Linda Neville
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Trustees Of Boston University
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Priority to AU55187/98A priority Critical patent/AU5518798A/en
Publication of WO1998024464A1 publication Critical patent/WO1998024464A1/fr

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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
    • C07K14/605—Glucagons
    • 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 is directed to specific antagonists of glucose-dependent insulinotropic polypeptide (GIP) This invention is also directed to treatment of non-insulin dependent diabetes through increasing glucose tolerance without requirement for increased serum insulin, the treatment of obesity by the administration of a GIP antagonist, the development of nonpeptide
  • GIP glucose-dependent insulinotropic polypeptide
  • GIP antagonist compounds and compositions
  • GIP glucose-dependent insulinotropic polypeptide
  • GLP-l glucagon like peptide-1 (7-36)(GLP-l)
  • GIP glucose-dependent insulinotropic polypeptide
  • glucagon like peptide-1 (7-36)(GLP-l) appear to fulfill the requirements to be considered physiological stimulants of postprandial insulin release (Dupre, et al 1973, J. Chn. Endocrinol. Metab., 37 826-828, Nauck, et al , 1989, J. Chn. Endocrinol. Metab., 69 6540662, Kreymann, et al 1987, Lancet, 2 1300-1304, Mojsov, et al , 1987, J. Chn. Invest., 79 616-619)
  • GIP and GLP- 1 are equally potent in their capacity to stimulate insulin release (Schmid, et al , 1990, Z Gastroenterol., 28 280-284, Suzuki, et al , 1990, Diabetes, 39 1320-1325), whereas others have suggested that GLP-1 possesses greater insulinotropic properties (Siegel, et al 1992, Eur. J. Chn. Invest. 22 154- 157, Shima, et al 1988, Regul. Pept., 22 245-252) Recently, using a putative specific antagonist to the GLP-1 receptor, exendin (9-39), Wang et al.
  • exendin might also displace GIP binding from its receptor and thereby reduce GIP-stimulated cyclic adenosine monophosphate (cAMP) generation (Wheeler, et al 1995, Endocrinology, 136 4629-4639, Gremlich, et al 1995, Diabetes, 44 1202-1208) Therefore, the antagonist properties of exendin (9-39) might not be limited to GLP-1
  • GIP glucose-dependent insulinotropic polypeptide
  • this invention provides alternative methods for treatment of non-insulin dependent diabetes which increase glucose tolerance without requirement for increased serum insulin, for treatment of obesity with a GIP antagonist which inhibits, blocks or reduces glucose absorption from the intestine of an animal, and for development of nonpeptide GIP antagonist compounds
  • this invention provides an antagonist of glucose-dependent insulinotropic polypeptide (GIP) consisting essentially of a 24-amino acid polypeptide corresponding to positions 7-30 of the sequence of GIP
  • GIP glucose-dependent insulinotropic polypeptide
  • this invention provides a method of treating non-insulin dependent diabetes mellitus in a patient comprising administering to the patient an antagonist of glucose-dependent insulinotropic polypeptide (GIP)
  • GIP glucose-dependent insulinotropic polypeptide
  • this invention provides a method of improving glucose tolerance in a mammal comprising administering to the mammal an antagonist of glucose- dependent insulinotropic polypeptide (GIP) Using a reporter L-cell line stably transfected with rat GIP receptor cDNA (LGIPR2), the inventors have identified a fragment of GIP [GIP (7-30)-NH 2 ] as a specific GIP receptor antagonist
  • This antagonist (referred to as ANTGIP) inhibited GIP-stimulated intracellular cAMP production in vitro, and ANTGIP competed with GIP for binding to cellular receptors, but did not complete with GLP-1 ANTGIP inhibited the GIP-dependent release of insulin in vivo, but ANTGIP had no effect on glucose-, GLP-1-, GIP-, and arginine-induced insulin release in anesthetized rats In conscious rats, ANTGIP inhibited postprandial insulin release, without significantly affecting the serum glucose concentration However, despite its inhibiting effect on insulin
  • Figure 1A and IB show cAMP-dependent ⁇ -galactosidase production by LGIPR2 cells in the presence of GIP or various GIP fragments
  • Figure 2 shows dose-dependent inhibition of ANTGIP on GIP-included cAMP-dependent ⁇ -galactosidase production in LGIPR2 cells
  • Figure 3 shows competition of 125 I-GIP and 125 I GLP-1 (inset) binding by GIP, GLP-1 and ANTGIP
  • Figure 4 shows plasma insulin concentrations ( ⁇ SE) in fasted anesthetized rats after 30 min of GIP, ANTGIP, or 0 9 NaCl infusion
  • Figure 5 shows plasma insulin concentrations ( ⁇ SE) in fasted anesthetized rats after a
  • Figure 7 shows plasma insulin level following oral glucose administration to rats with or without ANTGIP injection
  • Figure 8 shows plasma glucose level following oral glucose administration to rats with and without ANTGIP injection
  • Figure 9 shows the effects of the GIP receptor antagonist, ANTGIIP, on the absorption of free D-glucose from the lumen of the jejunal test segment
  • Glucose-dependent insulinotropic polypeptide is 42-amino acid hormone that was originally described as a inhibitor of acid secretion More recently, however, it has been shown to be potent stimulant for the release of insulin from the endocrine pancreas
  • GIP and GLP-1 are the most likely physiological insulinotropic peptides
  • GIP and GLP-1 possess significant insulinotropic properties, controversy exists regarding their relative physiological roles in stimulating insulin release Using a GLP-1 receptor antagonist exendin (9-39), Wang et al.
  • exendin (1995) detected a 50% decrease in postprandial insulin secretion in exendin-treated rats Administration of exendin also reduced 70% of insulin release following intraduodenal glucose infusion (Kolligs, et al , 1995, Diabetes, 44 16-19) Recent studies, however, have demonstrated that exendin also displaced GIP binding from its receptor, and inhibits cAMP generation in response to GIP stimulation (Wheeler, et al 1995, Gremlich, et al 1995) Therefore, the antagonist properties of exendin do not appear to be GLP- 1 specific
  • ANTGIP GIP (7-30)-NH 2
  • ANTGIP inhibited the cAMP response to GIP in a concentration-dependent manner (see Figure 2), and in ⁇ TC3 cells, the antagonist displaced GIP binding from its receptor (see Figure 3)
  • ANTGIP completely abolished the insulinotropic properties of GIP in fasted anesthetized rats, while not affecting GLP-1, glucose-, or arginine- stimulated insulin release indicating that this antagonist is GIP-specific ANTGIP alone demonstrated no stimulatory effect on insulin release or cAMP generation in either intact rats or LGIPR2 cells, indicating the absence of any agonist properties
  • GIP (7-30)-NH 2 is a specific receptor antagonist of naturally occurring GIP GIP (7-30)-NH 2 inhibits GIP-induced cAMP generation and insulin release, but does not affect the insulinotropic effects of other secretagogues such as glucose, arginine, and GLP-1.
  • NIDDM noninsulin dependent diabetes mellitus
  • a GIP antagonist according to this invention is any composition which interferes with biological action of GIP
  • Such compositions include antibodies specific for either GIP or GIP receptors, antisense RNA which hybridizes with mRNA encoding GIP or GIP receptor, or other genetic controls which knock out expression of GIP or GIP receptor GIP antagonists also include peptides or other small molecules which bind to the GIP receptor and block the cAMP response to GIP Suitable assays for antagonist activity are exemplified in Examples 1 and 2 below.
  • the inventors have now discovered a polypeptide fragment of GIP that is a specific GIP receptor antagonist While the 30-amino acid N-terminal fragment [GIP (l-30)-NH 2 ] was as effective in stimulating cAMP increase through GIP receptors as the parent hormone, a fragment missing the most N-terminal six amino acids [GIP (7-30)-NH 2 ] did not stimulate cAMP release in the same system Thus, the N-terminal hexamer appears to be important for functional GIP signaling GIP fragments missing the N-terminal 15 amino acids (e g , GIP (16-30)-NH 2 ) did not mimic GIP, but neither did they inhibit GIP-dependent effects Thus, the segment from amino acids 7-15 appears to be especially important in signaling through the GIP receptor Fragment GIP (10-30)-NH 2 was less effective as an antagonist, but retained some ability to affect GIP receptor activation, as indicated by partial agonist activity Thus, peptide antagonists would appear to require the segment from amino acids
  • GIP antagonists include with specific monoclonal antibodies (either naked or conjugated to cytotoxic agents) or specific activated cytotoxic immune cells Such antibodies or immune cells may be generated as reagents outside the body, or may be generated inside the body by vaccines which target GIP or GIP receptors
  • Antibodies which are specifically reactive with GIP or the hormone binding domain of GIP receptor, or antigenic recombinant peptide fragments of either of those proteins, may be obtained in a number of ways which will be readily apparent to those skilled in the art The known sequences of GIP (see Takeda, et al 1987, Proc. Natl. Acad.
  • GIP receptor can be used in conjunction with standard recombinant DNA technology to produce the desired antigenic peptides in recombinant systems (see, e g , Sanbrook et al )
  • Antigenic fragments of GIP or GIP receptor can be injected into an animal as a immunogen to elicit polyclonal antibody production Purification of the antibodies can be accomplished by selective binding from the serum, for instance by using cells transformed with DNA sequence encoding the respective proteins
  • the resultant polyclonal antisera may be used directly or may be purified by, for example, affinity absorption using recombinantly produced protein coupled to an insoluble support
  • monoclonal antibodies specifically immunoreactive with either GIP or the hormone binding domain of GIP receptor may be prepared according to well known methods (See, e g , Kohler and Milstein,
  • Immunogenic compositions according to this invention for use in active immunotherapy include recombinant antigenic fragments of GIP or GIP receptor prepared as described above and expression vectors (particularly recombinant viral vectors) which express antigenic fragments of GLP or GLP receptor
  • expression vectors can be prepared as described in Baschang, et al , U S Patent No 4,446,128, incorporated herein by reference, or Axel, et al , Pastan, et al , or Davis, et al , using the known sequences of GIP or GIP receptor
  • Still another GLP antagonist according to this invention is an expression vector containing an antisense sequence corresponding to all or part of an mRNA sequence encoding GIP or GIP receptor, inserted in opposite orientation into the vector after a promoter As a result, the inserted DNA will be transcribed to produce an RNA which is complementary to and capable of binding or hybridizing to the mRNA Upon binding to the GIP or GIP receptor mRNA, translation of the mRNA is prevented, and consequently the protein coded for by the mRNA is not produced Suitable antisense sequences can be readily selected by the skilled artisan from the sequences of GIP or GIP receptor cited above Production and use of antisense expression vectors is described in more detail in U S Patent 5, 107,065 and U S Patent 5, 190,931, both of which are incorporated herein by reference Alternative materials within the contemplation of the skilled artisan which function as antagonists of GLP in the procedures described in Examples 1 and 3-5 below may also be used in the therapeutic methods according to this invention
  • GLP (7-30)-NH 2 acts as a receptor antagonist of GLP, but also improves glucose tolerance contrary to the expected consequence of blocking GIP-dependent insulin secretion
  • a GIP receptor antagonist in accordance with the present invention inhibits, blocks or reduces glucose absorption from the intestine of an animal
  • therapeutic compositions containing GIP antagonists may be used in patients with noninsulin dependent diabetes mellitus (NIDDM) to improve tolerance to oral glucose or in animals, such as humans, to prevent, inhibit or reduce obesity by inhibiting, blocking or reducing glucose absorption from the intestine of the animal, as demonstrated herein
  • NIDDM noninsulin dependent diabetes mellitus
  • compositions according to this invention are preferably formulated in pharmaceutical compositions containing one or more GIP antagonists and a pharmaceutically acceptable carrier
  • the pharmaceutical composition may contain other components so long as the other components do not reduce the effectiveness of the GIP antagonist according to this invention so much that the therapy is negated
  • examples of such components include sweetening, flavoring, coloring, dispersing, disintegrating, binding, granulating, suspending, wetting, preservative and demulcent agents and the like
  • Pharmaceutically acceptable carriers are well known, and one skilled in the pharmaceutical art can easily select carriers suitable for particular routes for administration (Remington's Pharmaceutical Sciences. Mack Publishing Co , Easton, PA, 1985)
  • the GIP receptor antagonist of the present invention may be lyophilized using standard techniques known to those in this art
  • the lyophilized GLP receptor antagonists may then be reconstituted with, for example, suitable diluents such as normal saline, sterile water, glacial acetic acid, sodium acetate, combinations thereof and the like
  • suitable diluents such as normal saline, sterile water, glacial acetic acid, sodium acetate, combinations thereof and the like
  • the reconstituted GIP receptor antagonists in accordance with the present invention may be administered parenterally or orally and may further include preservatives or other acceptable inert components as mentioned hereinbefore
  • compositions containing any of the GIP antagonists according to this invention may be administered by parenteral (subcutaneously, intramuscularly, intravenously, intraperitoneally, intrapleurally, intravesicularly or intrathecally, topical, oral, rectal, or nasal route, as necessitated by choice of drug and disease
  • parenteral subcutaneously, intramuscularly, intravenously, intraperitoneally, intrapleurally, intravesicularly or intrathecally, topical, oral, rectal, or nasal route, as necessitated by choice of drug and disease
  • the dose used in a particular formulation or application will be determined by the requirements of the particular state of disease and the constraints imposed by the characteristics of capacities of the carrier materials
  • concentrations of the active agent in pharmaceutically acceptable carriers may range from 0 InM to lOO ⁇ M
  • the compositions described above may be combined or used together or in coordination with another therapeutic substance
  • Dose will depend on a variety of factors, including the therapeutic index of the drugs, disease type, patient age, patient weight, and tolerance of toxicity Dose will generally be chosen to achieve serum concentrations fro about 0 1 ⁇ g/ml to about 100 g/ml Preferably, initial dose levels will be selected based on their ability to achieve ambient concentrations shown to be effective in in-vitro models, such as that used to determine therapeutic index, and in-vivo models and in clinical trials, up to maximum tolerated levels Standard clinical procedure prefers that chemotherapy be tailored to the individual patient and the sytemic concentration of the chemotherapeutic agent be monitored regularly
  • the dose of a particular patient can be determined by the skilled clinician using standard pharmacological approaches in view of the above factors
  • the response to treatment may be monitored by analysis of blood or body fluid levels of the glucose or GIP or GIP antagonist according to this invention, measurement of activity if the antagonist or its levels in relevant tissues or monitoring disease state of the patient The skilled clinician will adjust the dose based on the response to treatment revealed by these
  • a method which comprises obtaining a DNA expression vector containing a cDNA sequence having the sequence of human GIP or GIP receptor mRNA which is operably linked to a promoter such that it will be expressed in antisense orientation, and transforming cells which express GLP or GLP receptor, respectively, with the DNA vector
  • the expression vector material is generally produced by culture of recombinant or transfected cells and formulated in a pharmacologically acceptable solution or suspension, which is usually a physiologically- compatible aqueous solution, or in coated tablets, tablets, capsules, suppositories, inhalation aerosols, or ampules, as described in the art, for example in U S Patent 4,446,128, incorporated herein by reference
  • the vector-containing composition is administered to a mammal exhibiting NLDDM in an amount sufficient to transect a substantial portion of the target cells of
  • the present invention also contemplates the use of the GIP antagonists and/or its properties to develop nonpeptide compounds which exhibit antagonist properties similar to the GIP polypeptide antagonists as herein described using techniques known those versed in the pharmaceutical industry
  • LGLPR2 cells are stably transfected with a cAMP-dependent promoter from the VIP gene fused to the bacterial lac Z gene When intracellular cAMP increases within these cells, lac Z gene transcription is activated, resulting in the accumulation of its product, ⁇ -galactosidase
  • the measurement of ⁇ -galactosidase in this system provided a convenient, inexpensive, and nonradioactive method for detecting changes in the levels of intracellular cAMP
  • LGLPR2 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) containing 4 5 g/L of glucose and 10% fetal calf serum For each assay, 10 5 cells/well were seeded onto 24- well plates After incubation overnight, peptides were added in various concentrations to the wells in the absence of 3-isobutyl-methylxanthine (IBMX) for 4 h, at which time maximal stimulation of ⁇ -galactosidase was determined The medium was then removed and wells rinsed once with phosphate-buffered saline (PBS) The plates were then blotted briefly and frozen overnight at -70 °C, and, after the addition of chlorophenol red- ⁇ -D-galactopyranoside, accumulated ⁇ -galactosidase was detected using a colorimet ⁇ c assay, as described previously (Usdin, et al , 1993, Endocrinology, 133 2861-2870) Prelimin
  • LGIPR2 cells were incubated in the presence of 10 "8 M GIP or different GIP fragments for 4 h, and ⁇ - galactosidase was measured as described herein and expressed in optical density (O D ) units
  • Figure 1A and IB show cyclic AMP-dependent ⁇ -galactosidase generation in LGIPR2 cells in response to incubation with different fragments of GIP Values are expressed as the mean ⁇ SE of quadruplicate measurements (*p ⁇ 0 01, compared to control)
  • Figure IB shows that peptide GIP (10-30)-NH 2 is an antagonist, albeit a weak one, as demonstrated by the reduction in GIP-stimulated ⁇ -gal levels when GIP (10-30)-NH 2 is present with GIP (1-42) compared to GIP (1-42) alone
  • GIP (10-30)-NH 2 also has agonist properties, as demonstrated by ⁇ -gal level of 0 39 O D ⁇ 0 03 stimulated by GIP (10-30)-
  • Binding studies were performed in either LGIPR2 or ⁇ TC3 cells to determine the relative affinities of GIP, ANTGIP, and GLP-1 for both GIP and GLP-1 receptors
  • GLP(7-37) and porcine GLP (5 ⁇ g each) were iodinated by the chloramine-T method and were purified using C- 18 cartridges (Sep-Pak®, Millipore, Milford, MA) using an acetonitrile gradient of 30-45%
  • the specific activity of radiolabeled peptides was 10-50 ⁇ Ci/mg (Hunter, et al , 1962, Nature, 194 495-498, Kieffer, et al , 1993, Can. J. Physiol.
  • the receptor binding buffer contained 138 mM NaCl, 5 6 mM KC1, 1 2 mM MgCl 2 , 2 6 mM CaCl 2 , 10 mM Hepes, 10 mM glucose, and 1% bovine serum albumin (BSA, fraction V, protease free, Sigma)
  • BSA bovine serum albumin
  • LGIPR2 GIP binding
  • ⁇ TC3 GLP-1 binding
  • Rats Male male Sprague-Dawley rats (250-350 g) were purchased from Charles River Co (Kingston, MA) For infusion studies, rats were fasted overnight and then anesthetized using intraperitoneal sodium pentobarbital The right jugular vein was cannulated with silicon polymer tubing (0 025 in I D , 0 047 in O D , Dow Corning Corporation, Midland, MI), as described by Xu and Melethil (21) The tubing was then connected to an infusion pump (Harvard Apparatus Co , Inc , Millis, MA), and freshly made 0 9% NaCl, 5% glucose, arginine, GIP, or GLP-1 (peptides and arginine dissolved in 0 9% NaCl) was infused at a rate of 0 1 ml/min Blood (0 5 ml each) was obtained at 0, 10, 20, and 30 min by translumbar vena cava puncture, as described by Winsett etal.
  • GLP-1 (0 4 nmol/kg), glucose (0 8 g/kg), or arginine (375 mg/kg) was infused, in the presence or absence of the antagonist for 30 min, as described by Wang et al.
  • ANTGLP 300 ng/kg or 0 9% saline solution
  • an oral glucose tolerance test was performed The test was done by administering a 40% glucose solution by oral gavage at a dose of 1 g per kg The volume administered to each rat was approximately 0 5 ml Blood was obtained at various time points for subsequent measurement of plasma insulin and glucose levels
  • the enclosed Figure 9 depicts the effects of the GLP receptor antagonist, ANTGIP, on the absorption of free D-glucose from the lumen of the jejunal test segment Data points are believed to represent the rate of glucose disappearance from the luminal perfusate corrected for fluid movement Results are expressed as the mean ⁇ SE of five experiments Statistical significance (*) is assigned if P ⁇ 0 05 As seen in the figure, a ANTGIP is believed to significantly reduce the absorption of D-glucose from the jejunal test segment throughout the entire 30-mini period of perfusion Thus, it is believed that one of the mechanisms by which GIP receptor antagonism may improve glucose tolerance is by decreasing intestinal glucose absorption

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Abstract

Dans l'une de ses réalisations, la présente invention concerne un antagoniste du polypeptide glucodépendant insulinotrope 'GIP' (Glucose-dependant insulinotropic polypeptide) qui est essentiellement constitué d'un polypeptide de 24 acides aminés correspondant aux positions 7 à 30 de la séquence du GIP. Selon une autre de ses réalisations, l'invention concerne une thérapie dirigée contre les diabètes non insulinodépendant et consistant en une administration du polypeptide glucodépendant insulinotrope 'GIP'. Selon encore une autre de ses réalisation, l'invention un procédé permettant d'améliorer la glucotolérance d'un mammifère et consistant en l'administration au mammifère concerné d'un antagoniste du polypeptide glucodépendant insulinotrope 'GIP'.
PCT/US1997/022418 1996-12-03 1997-12-03 Antagonistes specifiques du polypeptide glucodependant insulinotrope (gip) WO1998024464A1 (fr)

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000020592A1 (fr) * 1998-10-07 2000-04-13 Medical College Of Georgia Research Institute, Inc. Peptide glucodependant insulinotrope utilise comme hormone osteotrope
WO2001087341A1 (fr) * 2000-05-16 2001-11-22 Sanwa Kagaku Kenkyusho Co.,Ltd. Agents permettant de prevenir ou d'ameliorer l'insulino-resistance et/ou l'obesite
WO2003103697A2 (fr) * 2002-06-11 2003-12-18 Cell Therapeutics Scandinavia Ab Utilisation de composes ayant une activite gip dans le traitement de troubles associes a une perte anormale de cellules et/ou dans le traitement de l'obesite
EP1526864A2 (fr) * 2002-06-15 2005-05-04 Enteromed, Inc. Prevention et traitement d'une steatose hepatique non alcoolique (nafld), par antagonisme du recepteur du polypeptide insulinotropique gluco-dependant (gip)
EP1857818A1 (fr) * 2006-05-15 2007-11-21 DIGILAB BioVisioN GmbH Diagnostic et usages thérapeutiques des peptides pour les formes de diabète précoces de type 2 et les conditions correspondantes
EP2390264A1 (fr) 2005-02-11 2011-11-30 Amylin Pharmaceuticals Inc. Analogues de GIP et polypeptides hybrides de GIP aux propriétés sélectionnables
AU2009280015B2 (en) * 2008-08-07 2012-11-08 Ipsen Pharma S.A.S. Glucose-dependent insulinotropic polypeptide analogues
AU2009280012B2 (en) * 2008-08-07 2012-12-06 Ipsen Pharma S.A.S. Truncated analogues of glucose-dependent insulinotropic polypeptide
US8338368B2 (en) 2005-11-07 2012-12-25 Indiana University Research And Technology Corporation Glucagon analogs exhibiting physiological solubility and stability
US8450270B2 (en) 2008-06-17 2013-05-28 Indiana University Research And Technology Corporation Glucagon analogs exhibiting enhanced solubility and stability in physiological pH buffers
US8454971B2 (en) 2007-02-15 2013-06-04 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
US8507428B2 (en) 2010-12-22 2013-08-13 Indiana University Research And Technology Corporation Glucagon analogs exhibiting GIP receptor activity
US8546327B2 (en) 2008-06-17 2013-10-01 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
US8551946B2 (en) 2010-01-27 2013-10-08 Indiana University Research And Technology Corporation Glucagon antagonist-GIP agonist conjugates and compositions for the treatment of metabolic disorders and obesity
WO2014023923A2 (fr) 2012-08-30 2014-02-13 Universite Pierre Et Marie Curie (Paris 6) Traitement de l'arthrose par les hormones incrétines ou leurs analogues
US8669228B2 (en) 2007-01-05 2014-03-11 Indiana University Research And Technology Corporation Glucagon analogs exhibiting enhanced solubility in physiological pH buffers
US8703701B2 (en) 2009-12-18 2014-04-22 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
US8729017B2 (en) 2011-06-22 2014-05-20 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
US8778872B2 (en) 2010-06-24 2014-07-15 Indiana University Research And Technology Corporation Amide based glucagon superfamily peptide prodrugs
EP2769986A2 (fr) 2008-08-07 2014-08-27 Ipsen Pharma S.A.S. Analogues de polypeptide insulinotrope glucose-dependant (GIP) modifies a l'extremite N-terminale
US8859491B2 (en) 2011-11-17 2014-10-14 Indiana University Research And Technology Corporation Glucagon superfamily peptides exhibiting glucocorticoid receptor activity
US8969288B2 (en) 2008-12-19 2015-03-03 Indiana University Research And Technology Corporation Amide based glucagon and superfamily peptide prodrugs
US8980830B2 (en) 2007-10-30 2015-03-17 Indiana University Research And Technology Corporation Peptide compounds exhibiting glucagon antagonist and GLP-1 agonist activity
US8981047B2 (en) 2007-10-30 2015-03-17 Indiana University Research And Technology Corporation Glucagon antagonists
US9062124B2 (en) 2008-06-17 2015-06-23 Indiana University Research And Technology Corporation GIP-based mixed agonists for treatment of metabolic disorders and obesity
US9127088B2 (en) 2010-05-13 2015-09-08 Indiana University Research And Technology Corporation Glucagon superfamily peptides exhibiting nuclear hormone receptor activity
US9145451B2 (en) 2010-05-13 2015-09-29 Indiana University Research And Technology Corporation Glucagon superfamily peptides exhbiting G protein coupled receptor activity
US9150632B2 (en) 2009-06-16 2015-10-06 Indiana University Research And Technology Corporation GIP receptor-active glucagon compounds
US9156902B2 (en) 2011-06-22 2015-10-13 Indiana University Research And Technology Corporation Glucagon/GLP-1 receptor co-agonists
EP2987805A2 (fr) 2008-08-07 2016-02-24 Ipsen Pharma S.A.S. Analogues de polypeptide insulinotrope glucose-dépendant
WO2016034186A1 (fr) * 2014-09-05 2016-03-10 University Of Copenhagen Analogues peptidiques de gip
US9340600B2 (en) 2012-06-21 2016-05-17 Indiana University Research And Technology Corporation Glucagon analogs exhibiting GIP receptor activity
WO2017112824A3 (fr) * 2015-12-23 2017-08-10 Amgen Inc. Procédé de traitement ou d'amélioration de troubles métaboliques à l'aide de protéines de liaison au récepteur du peptide inhibiteur gastrique (gipr) en association avec des agonistes du glp-1
EP3124966A4 (fr) * 2014-03-24 2017-09-27 Kao Corporation Procédé d'évaluation ou de sélection d'inhibiteur d'élévation de gip
WO2018220123A1 (fr) 2017-05-31 2018-12-06 University Of Copenhagen Analogues peptidiques de gip à action prolongée
WO2018237097A1 (fr) * 2017-06-20 2018-12-27 Amgen Inc. Méthode de traitement ou de réduction de troubles métaboliques à l'aide de protéines de liaison au récepteur du peptide inhibiteur gastrique (gipr) en association avec des agonistes du glp-1
WO2020115048A1 (fr) 2018-12-03 2020-06-11 Antag Therapeutics Aps Analogues peptidiques de gip modifiés
US10905772B2 (en) 2017-01-17 2021-02-02 Amgen Inc. Method of treating or ameliorating metabolic disorders using GLP-1 receptor agonists conjugated to antagonists for gastric inhibitory peptide receptor (GIPR)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463564A (en) * 1994-09-16 1995-10-31 3-Dimensional Pharmaceuticals, Inc. System and method of automatically generating chemical compounds with desired properties
US5614492A (en) * 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5614492A (en) * 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US5463564A (en) * 1994-09-16 1995-10-31 3-Dimensional Pharmaceuticals, Inc. System and method of automatically generating chemical compounds with desired properties

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
AM. J. PHYSIOL., 1985, Vol. 249, KRARUP T. et al., "Responses to Molecular Heterogeneity of IR-GIP after Intraduodenal Glucose and Fat", pages E195-E200. *
AM. J. PHYSIOL., September 1996, Vol. 271, (3 Pt. 1), CHEESEMAN C.I. et al., "The Effect of GIP and Glucagon-Like Peptides on Intestinal Basolateral Membrane Hexose Transport", pages G447-G482. *
FEBS LETTERS, July 1984, Vol. 172, No. 2, MOODY J.M. et al., "The Isolation and Sequencing of Human Gastric Inhibitory Peptide (GIP)", pages 142-149. *
J. CLIN. INVEST., 01 December 1996, Vol. 98, No. 11, TSENG C.C. et al., "Postprandial Stimulation of Insulin Release by Glucose-Dependent Insulinotropic Polypeptide (GIP)", pages 2240-2445. *
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM, 1985, Vol. 61, No. 2, MAZZAFERRI E.L. et al., "Gastric Inhibitory Polypeptide Response to Nutrients in Caucasian and American Indians with Obesity and Noninsulin-Dependent Diabetes Mellitus", pages 313-321. *
REGULATORY PEPTIDES, 1992, Vol. 39, ROSSOWSKI W.J. et al., "Reduced Gastric Acid Inhibitory Effect of a pGIP(1-30)NH2 Fragment with Potent Pancreatic Amylase Inhibitory Activity", pages 9-17. *

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