Discovery and pharmacological effects of a novel GPR142 antagonist.
GPR142 is a G-protein-coupled receptor (GPCR), whose most potent and efficacious ligand has been reported as being the natural amino acid l-tryptophan. GPR142 is highly expressed in pancreatic β-cells and immune cells, suggesting the receptor may play a role in the pathogenesis and development of diabetes or inflammatory diseases. In a previous report, we developed GPR142 agonists as insulin secretagogues. In this report, we show the discovery of a selective, potent small-molecule GPR142 antagonist, CLP-3094, and its pharmacological characteristics. These data support targeting this receptor for the treatment of chronic inflammatory diseases.
a Biological Research Department , Daiichi Sankyo RD Novare Co. Ltd. , Tokyo , Japan.
Michiko
M
Murakoshi
b Pain & Neuroscience Laboratories, Research Function, R&D Division , Daiichi Sankyo Co. Ltd. , Tokyo , Japan.
Harumi
H
Kuwabara
c Biologics & Immuno-Oncology Laboratories Research Function , R&D Division , Daiichi Sankyo Co. Ltd. , Tokyo , Japan.
Miyuki
M
Nagasaki
d Department of Cardio-Metabolic Disorders , Amgen, Inc. , South San Francisco , CA , USA.
Yu Mei
YM
Xiong
d Department of Cardio-Metabolic Disorders , Amgen, Inc. , South San Francisco , CA , USA.
Jeff D
JD
Reagan
e Immunology & Inflammatory Disease Field , Asubio Pharma Co. Ltd. , Kobe , Japan.
Hiroaki
H
Maeda
c Biologics & Immuno-Oncology Laboratories Research Function , R&D Division , Daiichi Sankyo Co. Ltd. , Tokyo , Japan.
Futoshi
F
Nara
D001562:Benzimidazoles / Q000737:chemistry*; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D055808:Drug Discovery; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000627:therapeutic use
D001562:Benzimidazoles; C000619791:CLP-3094; C501537:GPR142 protein, human; D007328:Insulin; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries
GPR142 antagonist; KO mouse; anti-CII Ab-induced arthritis; inflammatory diseases; l-tryptophan