title: Optimization of the 4-aryl group of 4-aryl-pyridine glucagon antagonists: development of an efficient, alternative synthesis.
abstract: A narrow structure-activity relationship was established for the 4-aryl group in 4-aryl-pyridine glucagon antagonists, with only small substituents being well-tolerated, and only at the 3'- and 4'-positions. However, substitution with a 2'-hydroxy group gave a ca. 3-fold increase in activity (e.g., 4'-fluoro-2'-hydroxy analogue 33, IC50=190 nM). For efficient preparation of 2'-substituted phenylpyridines, a novel synthesis via pyrones and 4-methoxy-pyridines was developed.
authors.affiliation: Department of Chemistry Research, Bayer Research Center, 400Morgan Lane, West Haven, CT 06516, USA. roger.smith.b@bayer.com
authors.forename: Roger A
authors.initials: RA
authors.lastname: Smith
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hertzog
authors.forename: Martin H
authors.initials: MH
authors.lastname: Osterhout
authors.forename: Gaetan H
authors.initials: GH
authors.lastname: Ladouceur
authors.forename: Mary
authors.initials: M
authors.lastname: Korpusik
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bobko
authors.forename: J Howard
authors.initials: JH
authors.lastname: Jones
authors.forename: Kathleen
authors.initials: K
authors.lastname: Phelan
authors.forename: Romulo H
authors.initials: RH
authors.lastname: Romero
authors.forename: Thomas
authors.initials: T
authors.lastname: Hundertmark
authors.forename: Margit L
authors.initials: ML
authors.lastname: MacDougall
authors.forename: James N
authors.initials: JN
authors.lastname: Livingston
authors.forename: William R
authors.initials: WR
authors.lastname: Schoen
mesh_terms: D005934:Glucagon / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; D005934:Glucagon; C023666:pyridine