title: Discovery of trifluoromethyl(pyrimidin-2-yl)azetidine-2-carboxamides as potent, orally bioavailable TGR5 (GPBAR1) agonists: structure-activity relationships, lead optimization, and chronic in vivo efficacy.
abstract: Activation of the G-protein coupled receptor (GPCR) Takeda G-protein receptor 5 (TGR5), also known as G-protein bile acid receptor 1 (GPBAR1), has been shown to play a key role in pathways associated with diabetes, metabolic syndrome, and autoimmune disease. Nipecotamide 5 was identified as an attractive starting point after a high-throughput screen (HTS) for receptor agonists. A comprehensive hit-to-lead effort culminated in the discovery of 45h as a potent, selective, and bioavailable TGR5 agonist to test in preclinical metabolic disease models. In genetically obese mice (ob/ob), 45h was as effective as a dipeptidyl peptidase-4 (DPP-4) inhibitor at reducing peak glucose levels in an acute oral glucose tolerance test (OGTT), but this effect was lost upon chronic dosing.
authors.affiliation: Departments of †Medicinal Chemistry, ‡Drug Discovery Biology, §Pharmacology, ∥Pharmacokinetics, and ⊥Structural Biology, Genomics Institute of the Novartis Research Foundation , 10675 John Jay Hopkins Drive, San Diego, California 92121, United States.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Phillips
authors.forename: Wenqi
authors.initials: W
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Guobao
authors.initials: G
authors.lastname: Zhang
authors.forename: Isabelle K
authors.initials: IK
authors.lastname: Lerario
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Lau
authors.forename: Jiqing
authors.initials: J
authors.lastname: Jiang
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Nguyen
authors.forename: B Ganesh
authors.initials: BG
authors.lastname: Bhat
authors.forename: Carol
authors.initials: C
authors.lastname: Trotter
authors.forename: Heather
authors.initials: H
authors.lastname: Sullivan
authors.forename: Gustav
authors.initials: G
authors.lastname: Welzel
authors.forename: Jannine
authors.initials: J
authors.lastname: Landry
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.forename: Sean B
authors.initials: SB
authors.lastname: Joseph
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: W Perry
authors.initials: WP
authors.lastname: Gordon
authors.forename: Wendy
authors.initials: W
authors.lastname: Richmond
authors.forename: Kevin
authors.initials: K
authors.lastname: Johnson
authors.forename: Angela
authors.initials: A
authors.lastname: Bretz
authors.forename: Badry
authors.initials: B
authors.lastname: Bursulaya
authors.forename: Shifeng
authors.initials: S
authors.lastname: Pan
authors.forename: Peter
authors.initials: P
authors.lastname: McNamara
authors.forename: H Martin
authors.initials: HM
authors.lastname: Seidel
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D052216:Glucagon-Like Peptide 1 / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: C473772:GPBAR1 protein, human; D007004:Hypoglycemic Agents; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D052216:Glucagon-Like Peptide 1