title: Discovery and optimization of a novel series of GPR142 agonists for the treatment of type 2 diabetes mellitus.
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.
authors.affiliation: Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, USA. mlizarza@amgen.com
authors.forename: Mike
authors.initials: M
authors.lastname: Lizarzaburu
authors.forename: Simon
authors.initials: S
authors.lastname: Turcotte
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Du
authors.forename: Jason
authors.initials: J
authors.lastname: Duquette
authors.forename: Angela
authors.initials: A
authors.lastname: Fu
authors.forename: Jonathan
authors.initials: J
authors.lastname: Houze
authors.forename: Leping
authors.initials: L
authors.lastname: Li
authors.forename: Jinqian
authors.initials: J
authors.lastname: Liu
authors.forename: Michiko
authors.initials: M
authors.lastname: Murakoshi
authors.forename: Kozo
authors.initials: K
authors.lastname: Oda
authors.forename: Ryo
authors.initials: R
authors.lastname: Okuyama
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
authors.forename: Jeff
authors.initials: J
authors.lastname: Reagan
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010649:Phenylalanine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C501537:GPR142 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D010649:Phenylalanine