title: Nonbenzamidine tetrazole derivatives as factor Xa inhibitors.
abstract: Factor Xa (fXa) is an important serine protease that holds the central position linking the intrinsic and extrinsic activation mechanisms in the blood coagulation cascade. Therefore, inhibition of fXa has potential therapeutic applications in the treatments of both arterial and venous thrombosis. Herein we describe a series of tetrazole fXa inhibitors containing benzamidine mimics as the P(1) substrate, of which the aminobenzisoxazole moiety was found to be the most potent benzamidine mimic. SR374 (12) inhibits fXa with a K(i) value of 0.35 nM and is very selective for fXa over thrombin and trypsin.
authors.affiliation: Bristol-Myers Squibb Co., PO Box 80500, Wilmington, DE 19880-0500, USA. mimi.quan@bms.com
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Ellis
authors.forename: Ming Y
authors.initials: MY
authors.lastname: He
authors.forename: Ann Y
authors.initials: AY
authors.lastname: Liauw
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Woerner
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Wright
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000818:Animals; D001682:Biological Availability; D004285:Dogs; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D018716:Molecular Mimicry; D011487:Protein Conformation; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000494:pharmacology
chemical_list: D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D013777:Tetrazoles; D014361:Trypsin Inhibitors; D013917:Thrombin