title: Design and synthesis of isoxazoline derivatives as factor Xa inhibitors. 2.
abstract: Intravascular clot formation is an important factor in a number of cardiovascular diseases. 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 thrombin activation. Herein we report a series of isoxazoline derivatives which are potent FXa inhibitors. Optimization of the side chain at the quaternary position of the isoxazoline ring led to SK549 which showed subnanomolar FXa potency (K(i) 0.52 nM). SK549 shows good selectivity for FXa compared to thrombin and trypsin, potent antithrombotic effect in the rabbit arterio-venous thrombosis model, and improved pharmacokinetics relative to other compounds evaluated from this series.
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: C D
authors.initials: CD
authors.lastname: Ellis
authors.forename: A Y
authors.initials: AY
authors.lastname: Liauw
authors.forename: R S
authors.initials: RS
authors.lastname: Alexander
authors.forename: R M
authors.initials: RM
authors.lastname: Knabb
authors.forename: G
authors.initials: G
authors.lastname: Lam
authors.forename: M R
authors.initials: MR
authors.lastname: Wright
authors.forename: P C
authors.initials: PC
authors.lastname: Wong
authors.forename: R R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: D000818:Animals; D001166:Arteriovenous Shunt, Surgical; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004285:Dogs; 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; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000188:drug therapy; D014357:Trypsin / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D007555:Isoxazoles; C120785:SK 549; D013777:Tetrazoles; D014361:Trypsin Inhibitors; D014357:Trypsin; D013917:Thrombin