WO2005120474A3 - Phophodiesterase 10a inhibitors to amplify the action of glp1-mimetics or dpp-iv inhibitors in diabetes - Google Patents

Phophodiesterase 10a inhibitors to amplify the action of glp1-mimetics or dpp-iv inhibitors in diabetes Download PDF

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Publication number
WO2005120474A3
WO2005120474A3 PCT/BE2005/000091 BE2005000091W WO2005120474A3 WO 2005120474 A3 WO2005120474 A3 WO 2005120474A3 BE 2005000091 W BE2005000091 W BE 2005000091W WO 2005120474 A3 WO2005120474 A3 WO 2005120474A3
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WIPO (PCT)
Prior art keywords
inhibitors
glp
diabetes
cells
pdel0a
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PCT/BE2005/000091
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French (fr)
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WO2005120474A2 (en
Inventor
Frans Schuit
Original Assignee
Leuven K U Res & Dev
Frans Schuit
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Application filed by Leuven K U Res & Dev, Frans Schuit filed Critical Leuven K U Res & Dev
Publication of WO2005120474A2 publication Critical patent/WO2005120474A2/en
Publication of WO2005120474A3 publication Critical patent/WO2005120474A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K38/26—Glucagons

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a new method for prevention and treatment of type 2 diabetes based on administration of inhibitors of phosphodiesterase 10A (PDE l0A) expression or PDEl0A activity in combination with agents that enhance or mimic GLP-1 signalling in the beta cell, long-acting GLP-1 analogs like exendin-4 or inhibitors of GLP-1 breakdown (DPP-­IV inhibitors). The invention is based upon the original findings that the cAMP­phosphodiesterase (PDE) isoform 10A, an enzyme that degrades cAMP with high affinity and that so far was mainly associated with brain function is not only expressed in brain but also in endocrine cells like pancreatic islets of Langerhans, the site of insulin secretion, as well as in pancreatic beta cell lines (MIN6 and INS 1). This expression was detected both at the Mrna level (real-time quantitative RT-PCR or microarray analysis), and protein as evidenced by Western blots with an affinity-purified rabbit polyclonal antibody. The high abundance of PDEl0A in neuro-endocrine cell types (brain, adrenal gland, pituitary, islets of Langerhans) which demonstrates a clear role for PDElOA in hormone secretion. Furthermore it was found that PDElOA is induced by food intake in mouse islets and severely (70%) lowered by overnight fasting. As PDE l0A was specifically down-regulated (mRNA-level) in genetically modified mice that do not express functional GLP-1 or GIP receptors in beta cells (DIRKO mice), we claim in~retin receptors induce the mRNA in beta cells. This was further demonstrated in INS1 cells, where PDEl0A is induced by 6-24 exposure to agents that raise cAMP in the cells, such as forskolin, IBMX and GLP-l. Based on these observation a combination medicament has been developed combining the PDEl0A inhibitor, Dipyridamole or derivatives thereof or the PDE10 inhibitor, papaverine, to remarka~ y enhance the effect of agents that enhance or mimic GLP-1 signalling in the beta cell, Long­acting GLP-1 analogs like exendin-4 or inhibitors of GLP-1 breakdown (DPP-IV inhibitors) to treat a disorder of impaired insulin secretion such as type 2 diabetes, maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (MT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X and more particularly type 2 diabetes.
PCT/BE2005/000091 2004-06-05 2005-06-06 Phophodiesterase 10a inhibitors to amplify the action of glp1-mimetics or dpp-iv inhibitors in diabetes WO2005120474A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0412526.6 2004-06-05
GB0412526A GB0412526D0 (en) 2004-06-05 2004-06-05 Type 2 diabetes

Publications (2)

Publication Number Publication Date
WO2005120474A2 WO2005120474A2 (en) 2005-12-22
WO2005120474A3 true WO2005120474A3 (en) 2006-03-23

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PCT/BE2005/000091 WO2005120474A2 (en) 2004-06-05 2005-06-06 Phophodiesterase 10a inhibitors to amplify the action of glp1-mimetics or dpp-iv inhibitors in diabetes

Country Status (2)

Country Link
GB (1) GB0412526D0 (en)
WO (1) WO2005120474A2 (en)

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EA200801551A1 (en) * 2006-01-20 2009-02-27 Смитклайн Бичем Корпорейшн USE OF SULPHONAMIDE DERIVATIVES IN THE TREATMENT OF METABOLISM AND NERVOUS SYSTEM DISORDERS
CN108524505A (en) 2009-03-13 2018-09-14 安吉奥斯医药品有限公司 Method and composition for cell Proliferation associated disease
EP2417123A2 (en) 2009-04-06 2012-02-15 Agios Pharmaceuticals, Inc. Therapeutic compositions and related methods of use
CN102481300B (en) 2009-06-29 2015-04-15 安吉奥斯医药品有限公司 Therapeutic compounds and compositions
ES2594402T3 (en) 2009-10-21 2016-12-20 Agios Pharmaceuticals, Inc. Methods and compositions for disorders related to cell proliferation
WO2011088524A1 (en) * 2010-01-25 2011-07-28 Monash University Methods for regulating blood glucose levels
MX2013006900A (en) 2010-12-17 2013-10-17 Agios Pharmaceuticals Inc Novel n- (4- (azetidine - 1 - carbonyl) phenyl) - (hetero - ) arylsulfonamide derivatives as pyruvate kinase m2 (pmk2) modulators.
WO2012088314A1 (en) 2010-12-21 2012-06-28 Agios Pharmaceuticals, Inc. Bicyclic pkm2 activators
TWI549947B (en) 2010-12-29 2016-09-21 阿吉歐斯製藥公司 Therapeutic compounds and compositions
CA2834692A1 (en) 2011-05-03 2012-11-08 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
PL3406251T3 (en) 2011-05-03 2024-04-29 Agios Pharmaceuticals, Inc. Pyruvate kinase activators for use in therapy
CN102827073A (en) 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 Therapeutically active compositions and application methods thereof
CN102827170A (en) 2011-06-17 2012-12-19 安吉奥斯医药品有限公司 Active treatment compositions and use method thereof
EP2804603A1 (en) * 2012-01-10 2014-11-26 President and Fellows of Harvard College Beta-cell replication promoting compounds and methods of their use
US9474779B2 (en) 2012-01-19 2016-10-25 Agios Pharmaceuticals, Inc. Therapeutically active compositions and their methods of use
US9579324B2 (en) 2013-07-11 2017-02-28 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
CA2917671A1 (en) 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. 2,4-or 4,6-diaminopyrimidine compounds as idh2 mutants inhibitors for the treatment of cancer
WO2015003360A2 (en) 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
WO2015003355A2 (en) 2013-07-11 2015-01-15 Agios Pharmaceuticals, Inc. Therapeutically active compounds and their methods of use
US20150031627A1 (en) 2013-07-25 2015-01-29 Agios Pharmaceuticals, Inc Therapeutically active compounds and their methods of use
KR20240010105A (en) 2014-03-14 2024-01-23 아지오스 파마슈티컬스 아이엔씨. Pharmaceutical compositions of therapeutically active compounds
PT3307271T (en) 2015-06-11 2023-10-10 Agios Pharmaceuticals Inc Methods of using pyruvate kinase activators
LT3362065T (en) 2015-10-15 2024-07-25 Les Laboratoires Servier Combination therapy comprising ivosidenib, cytarabine and daunorubicin or idarubicin for treating acute myelogenous leukemia
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US10980788B2 (en) 2018-06-08 2021-04-20 Agios Pharmaceuticals, Inc. Therapy for treating malignancies

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GB0412526D0 (en) 2004-07-14

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