Discovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus

Mike Lizarzaburu; Simon Turcotte; Xiaohui Du; Jason Duquette; Angela Fu; Jonathan Houze; Leping Li; Jinqian Liu; Michiko Murakoshi; Kozo Oda; Ryo Okuyama; Futoshi Nara; Jeff Reagan; Ming Yu; Julio C Medina

doi:10.1016/j.bmcl.2012.07.063

Discovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus

Bioorg Med Chem Lett. 2012 Sep 15;22(18):5942-7. doi: 10.1016/j.bmcl.2012.07.063. Epub 2012 Jul 23.

Authors

Mike Lizarzaburu¹, Simon Turcotte, Xiaohui Du, Jason Duquette, Angela Fu, Jonathan Houze, Leping Li, Jinqian Liu, Michiko Murakoshi, Kozo Oda, Ryo Okuyama, Futoshi Nara, Jeff Reagan, Ming Yu, Julio C Medina

Affiliation

¹ Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA. [email protected]

PMID: 22884988
DOI: 10.1016/j.bmcl.2012.07.063

Abstract

The discovery and initial optimization of a series of phenylalanine based agonists for GPR142 is described. The structure-activity-relationship around the major areas of the molecule was explored to give agonists 90 times more potent than the initial HTS hit in a human GPR142 inositol phosphate accumulation assay. Removal of CYP inhibition by exploration of the pyridine A-ring is also described.

MeSH terms

Animals
Diabetes Mellitus, Type 2 / drug therapy*
Dose-Response Relationship, Drug
Drug Discovery*
Humans
Hypoglycemic Agents / chemical synthesis
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology*
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Phenylalanine / chemical synthesis
Phenylalanine / chemistry
Phenylalanine / pharmacology*
Rats
Receptors, G-Protein-Coupled / agonists*
Structure-Activity Relationship

Substances

GPR142 protein, human
Hypoglycemic Agents
Receptors, G-Protein-Coupled
Phenylalanine