Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex

被引:50
作者
South, MS
Case, BL
Wood, RS
Jones, DE
Hayes, MJ
Girard, TJ
Lachance, RM
Nicholson, NS
Clare, M
Stevens, AM
Stegeman, RA
Stallings, WC
Kurumbail, RG
Parlow, JJ
机构
[1] Pharmacia Corp, Dept Med & Combinatorial Chem, St Louis, MO 63167 USA
[2] Pharmacia Corp, Dept Cardiovasc & Metab Dis, St Louis, MO 63167 USA
[3] Pharmacia Corp, Dept Cardiovasc Pharmacol, Skokie, IL 60077 USA
[4] Pharmacia Corp, Struct & Computat Chem, Skokie, IL 60077 USA
[5] Pharmacia Corp, Struct & Computat Chem, St Louis, MO 63198 USA
关键词
D O I
10.1016/S0960-894X(03)00410-4
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor Vila complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P-2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P-1 and P-3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with > 6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis. (C) 2003 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:2319 / 2325
页数:7
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