Novel potent and selective thrombin inhibitors based on a central 1,4-benzoxazin-3(4H)-one scaffold.
Novel thrombin inhibitors with the central 1,4-benzoxazine-3(4 H)-one scaffold, benzamidine P1 arginine side chain mimetic and various P3 moieties are described. 3-(Benzyl(2-(4-carbamimidoylbenzyl)-4-methyl-3-oxo-3,4-dihydro-2 H-1,4-benzoxazin-7-yl)amino)-3-oxopropanoic acid (7b), the most potent compound in the series, exhibited a K i of 2.6 nM in vitro for thrombin and high selectivity against trypsin and factor Xa.
Ilas
Janez
J
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
Tomasić
Tihomir
T
Kikelj
Danijel
D
D048588:Benzoxazines / Q000138:chemical synthesis* / Q000737:chemistry; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014357:Trypsin / Q000737:chemistry; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry
C529823:3-(benzyl(2-(4-carbamimidoylbenzyl)-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl)amino)-3-oxopropanoic acid; D048588:Benzoxazines; D065427:Factor Xa Inhibitors; D014361:Trypsin Inhibitors; D014357:Trypsin; D013917:Thrombin; D015951:Factor Xa