title: Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 1.
abstract: Thrombosis is a major cause of mortality in the industrialized world. Therefore, the prevention of blood coagulation has become a major target for new therapeutic agents. One attractive approach is the inhibition of factor Xa (FXa), the enzyme directly responsible for prothrombin activation. We report a series of novel biaryl-substituted isoxazoline derivatives in which the biaryl moiety was designed to interact with the S(4) aryl-binding domain of the FXa active site. Several of the compounds herein have low nanomolar affinity for FXa, have good in vitro selectivity for FXa, and show potent antithrombotic efficacy in vivo. The three most potent compounds (33, 35, and 37) have inhibition constants for human FXa of 3.9, 2.3, and 0.83 nM, respectively, and ID(50)'s ranging from 0.15 to 0.26 micromol/kg/h in the rabbit arterio-venous thrombosis model.
authors.affiliation: DuPont Pharmaceuticals Company, Experimental Station, P.O. Box 80500, Wilmington, Delaware 19880-0500, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Quan
authors.forename: A Y
authors.initials: AY
authors.lastname: Liauw
authors.forename: C D
authors.initials: CD
authors.lastname: Ellis
authors.forename: J R
authors.initials: JR
authors.lastname: Pruitt
authors.forename: D J
authors.initials: DJ
authors.lastname: Carini
authors.forename: L L
authors.initials: LL
authors.lastname: Bostrom
authors.forename: P P
authors.initials: PP
authors.lastname: Huang
authors.forename: K
authors.initials: K
authors.lastname: Harrison
authors.forename: R M
authors.initials: RM
authors.lastname: Knabb
authors.forename: M J
authors.initials: MJ
authors.lastname: Thoolen
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001665:Binding Sites; D001713:Biphenyl Compounds; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D011817:Rabbits; D013329:Structure-Activity Relationship; D013927:Thrombosis / Q000188:drug therapy
chemical_list: C120782:3-(3-(aminoiminomethyl)phenyl)-5-(((2'-(aminosulfonyl)(1,1'-biphenyl)-4-yl)amino)carbonyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; C120784:3-(3-(aminoiminomethyl)phenyl)-5-(((5--(2-(aminosulfonyl)phenyl)-2-pyridinyl)amino)carbonyl)-4,5-dihydro-5-isoxazoleacetic acid methyl ester; D000085:Acetates; D001713:Biphenyl Compounds; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007555:Isoxazoles; C120783:SF 324