title: Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control.
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.
authors: Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA. gsemple@arenapharm.com
authors: Graeme
authors: G
authors: Semple
authors: Albert
authors: A
authors: Ren
authors: Beatriz
authors: B
authors: Fioravanti
authors: Guillherme
authors: G
authors: Pereira
authors: Imelda
authors: I
authors: Calderon
authors: Karoline
authors: K
authors: Choi
authors: Yifeng
authors: Y
authors: Xiong
authors: Young-Jun
authors: YJ
authors: Shin
authors: Tawfik
authors: T
authors: Gharbaoui
authors: Carleton R
authors: CR
authors: Sage
authors: Michael
authors: M
authors: Morgan
authors: Charles
authors: C
authors: Xing
authors: Zhi-Liang
authors: ZL
authors: Chu
authors: James N
authors: JN
authors: Leonard
authors: Andrew J
authors: AJ
authors: Grottick
authors: Hussein
authors: H
authors: Al-Shamma
authors: Yin
authors: Y
authors: Liang
authors: Keith T
authors: KT
authors: Demarest
authors: Robert M
authors: RM
authors: Jones
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D055808:Drug Discovery; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: C000617192:APD668; C521085:AR 231453; D001786:Blood Glucose; D019086:Bridged Bicyclo Compounds, Heterocyclic; C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D010069:Oxadiazoles; D011720:Pyrazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D005947:Glucose