title: Synthesis and structure-activity relationship of dihydrobenzofuran derivatives as novel human GPR119 agonists.
abstract: Through appropriate medicinal chemistry design tactics and computer-assisted conformational modeling, the initial lead A was evolved into a series of dihydrobenzofuran derivatives 3 as potent GPR119 agonists. This Letter describes the optimization of general structure 3, including the substituent(s) on dihydrobenzofuran, the R(1) attachment on right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R(2). The efforts led to the identification of compounds 13c and 24 as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles.
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States. Electronic address: xiang-yang.ye@bms.com.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Ye
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Morales
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: CADD, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.affiliation: Leads Discovery and Optimization, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Malmstrom
authors.affiliation: Leads Discovery and Optimization, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Abousleiman
authors.affiliation: Department of Biology, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Larisa
authors.initials: L
authors.lastname: Sereda
authors.affiliation: Bioanalytical and Discovery Analytical Sciences, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Atsu
authors.initials: A
authors.lastname: Apedo
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Robl
authors.affiliation: Department of Biology, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Keith J
authors.initials: KJ
authors.lastname: Miller
authors.affiliation: Department of Biology, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: John
authors.initials: J
authors.lastname: Krupinski
authors.affiliation: Department of Chemistry, Research & Development, Bristol-Myers Squibb Co., PO Box 5400, Princeton, NJ 08543, United States.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Wacker
mesh_terms: D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; C519854:GPR119 protein, human; D043562:Receptors, G-Protein-Coupled
keywords: Agonist; GPR119; Type 2 diabetes