title: Nonbenzamidine acylsulfonamide tissue factor-factor VIIa inhibitors.
abstract: Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P' binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype.
authors.affiliation: Bristol-Myers Squibb R&D, Pennington, NJ 08534, United States. peter.glunz@bms.com
authors.forename: Peter W
authors.initials: PW
authors.lastname: Glunz
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zou
authors.forename: Indawati
authors.initials: I
authors.lastname: Delucca
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Nirschl
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Weigelt
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.forename: Rushith
authors.initials: R
authors.lastname: Anumula
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: Mark
authors.initials: M
authors.lastname: Harpel
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.forename: Robert
authors.initials: R
authors.lastname: Knabb
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
mesh_terms: D001550:Benzamidines; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D001550:Benzamidines; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D015942:Factor VIIa
keywords: Factor VIIa; Serine protease inhibitors; Structure-based design; TF-FVIIa inhibitor; Tissue factor