title: Aminoisoquinolines: design and synthesis of an orally active benzamidine isostere for the inhibition of factor XA.
abstract: The design, synthesis and SAR of sulfonamidopyrrolidinone fXa inhibitors incorporating a new benzamidine isostere, namely aminoisoquinolines, is described. These inhibitors have higher Caco-2 cell permeability than comparable benzamidines and attain higher levels of exposure upon oral dosing. The most potent member 14b (fXa Ki=6 nM) is selective against other serine proteases of interest (>600 fold).
authors.affiliation: Department of Medicinal Chemistry, Rhône-Poulenc Rorer, Collegeville, PA 19426, USA.
authors.forename: Y M
authors.initials: YM
authors.lastname: Choi-Sledeski
authors.forename: M R
authors.initials: MR
authors.lastname: Becker
authors.forename: D M
authors.initials: DM
authors.lastname: Green
authors.forename: R
authors.initials: R
authors.lastname: Davis
authors.forename: W R
authors.initials: WR
authors.lastname: Ewing
authors.forename: H J
authors.initials: HJ
authors.lastname: Mason
authors.forename: C
authors.initials: C
authors.lastname: Ly
authors.forename: A
authors.initials: A
authors.lastname: Spada
authors.forename: G
authors.initials: G
authors.lastname: Liang
authors.forename: D
authors.initials: D
authors.lastname: Cheney
authors.forename: J
authors.initials: J
authors.lastname: Barton
authors.forename: V
authors.initials: V
authors.lastname: Chu
authors.forename: K
authors.initials: K
authors.lastname: Brown
authors.forename: D
authors.initials: D
authors.lastname: Colussi
authors.forename: R
authors.initials: R
authors.lastname: Bentley
authors.forename: R
authors.initials: R
authors.lastname: Leadley
authors.forename: C
authors.initials: C
authors.lastname: Dunwiddie
authors.forename: H W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D004285:Dogs; D065427:Factor Xa Inhibitors; D007546:Isoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D007546:Isoquinolines; D015842:Serine Proteinase Inhibitors