title: Activation of the G-protein-coupled receptor 119: a conformation-based hypothesis for understanding agonist response.
abstract: The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.
authors.affiliation: Department of Medicinal Chemistry, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, United States. kim.f.mcclure@pfizer.com
authors.forename: Kim F
authors.initials: KF
authors.lastname: McClure
authors.forename: Etzer
authors.initials: E
authors.lastname: Darout
authors.forename: Cristiano R W
authors.initials: CR
authors.lastname: Guimarães
authors.forename: Michael P
authors.initials: MP
authors.lastname: DeNinno
authors.forename: Vincent
authors.initials: V
authors.lastname: Mascitti
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Munchhof
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Robinson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kohrt
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Harris
authors.forename: Dianna E
authors.initials: DE
authors.lastname: Moore
authors.forename: Bryan
authors.initials: B
authors.lastname: Li
authors.forename: Lacey
authors.initials: L
authors.lastname: Samp
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Lefker
authors.forename: Kentaro
authors.initials: K
authors.lastname: Futatsugi
authors.forename: Daniel
authors.initials: D
authors.lastname: Kung
authors.forename: Paul D
authors.initials: PD
authors.lastname: Bonin
authors.forename: Peter
authors.initials: P
authors.lastname: Cornelius
authors.forename: Ruduan
authors.initials: R
authors.lastname: Wang
authors.forename: Eben
authors.initials: E
authors.lastname: Salter
authors.forename: Sam
authors.initials: S
authors.lastname: Hornby
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D006801:Humans; D008968:Molecular Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000037:antagonists & inhibitors; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D053961:Azabicyclo Compounds; C519854:GPR119 protein, human; C532423:GPR119 protein, rat; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; C558748:isopropyl 8-(5-methyl-6-(2-methylpyridin-3-yloxy)pyrimidin-4-yloxy)-6-oxa-3-azabicyclo(3.2.1)octane-3-carboxylate; C558747:isopropyl 9-((5-methyl-6-((2-methylpyridin-3-yl)oxy)pyrimidin-4-yl)oxy)-3-oxa-7-azabicyclo(3.3.1)nonane-7-carboxylate