1. Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control.
- Author
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Semple G, Ren A, Fioravanti B, Pereira G, Calderon I, Choi K, Xiong Y, Shin YJ, Gharbaoui T, Sage CR, Morgan M, Xing C, Chu ZL, Leonard JN, Grottick AJ, Al-Shamma H, Liang Y, Demarest KT, and Jones RM
- Subjects
- Animals, Bridged Bicyclo Compounds, Heterocyclic chemical synthesis, Bridged Bicyclo Compounds, Heterocyclic chemistry, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Disease Models, Animal, Glucose metabolism, Hypoglycemic Agents chemical synthesis, Hypoglycemic Agents chemistry, Molecular Structure, Oxadiazoles chemistry, Oxadiazoles pharmacology, Pyrazoles chemistry, Pyrazoles pharmacology, Pyrimidines chemistry, Pyrimidines pharmacology, Rats, Rats, Zucker, Blood Glucose drug effects, Drug Discovery, Hypoglycemic Agents pharmacology, Receptors, G-Protein-Coupled agonists
- Abstract
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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