title: 3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists.
abstract: The design, synthesis, and structure-activity relationship (SAR) for a series of β-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.
authors.affiliation: Merck Research Laboratories, Merck & Co., Inc., 126 E. Lincoln Ave., PO Box 2000, Rahway, NJ 07065-0900, USA. shawn_walsh@merck.com
authors.forename: Shawn P
authors.initials: SP
authors.lastname: Walsh
authors.forename: Alexandra
authors.initials: A
authors.lastname: Severino
authors.forename: Changyou
authors.initials: C
authors.lastname: Zhou
authors.forename: Jiafang
authors.initials: J
authors.lastname: He
authors.forename: Gui-Bai
authors.initials: GB
authors.lastname: Liang
authors.forename: Carina P
authors.initials: CP
authors.lastname: Tan
authors.forename: Jin
authors.initials: J
authors.lastname: Cao
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Lihu
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D003500:Cyclization; D004195:Disease Models, Animal; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007515:Islets of Langerhans / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*
chemical_list: C473036:Ffar1 protein, mouse; D007004:Hypoglycemic Agents; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; C029658:propionic acid