发现一种口服有效的凝血因子Xa抑制剂，其含有中性P1配体。

Discovery of an orally efficacious inhibitor of coagulation factor Xa which incorporates a neutral P1 ligand.

作者信息

Choi-Sledeski Yong Mi, Kearney Robert, Poli Gregory, Pauls Henry, Gardner Charles, Gong Yong, Becker Michael, Davis Roderick, Spada Alfred, Liang Guyan, Chu Valeria, Brown Karen, Collussi Dennis, Leadley Robert, Rebello Sam, Moxey Phillip, Morgan Suzanne, Bentley Ross, Kasiewski Charles, Maignan Sebastien, Guilloteau Jean-Pierre, Mikol Vincent

机构信息

Department of Medicinal Chemistry and Department of Biology, Aventis Pharmaceuticals, Route 202-206, Bridgewater, New Jersey 08807-0800, USA.

出版信息

J Med Chem. 2003 Feb 27;46(5):681-4. doi: 10.1021/jm020384z.

DOI:10.1021/jm020384z

PMID:12593648

Abstract

The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.

摘要

描述了酮哌嗪基甲基氮杂吲哚因子Xa抑制剂的发现及其构效关系。构效数据表明这类抑制剂并非以经典模式结合，这一点通过X射线晶体结构得以证实，该结构显示中性卤代芳烃结合在S(1)亚位点。最具活性的氮杂吲哚33（RPR209685）对相关丝氨酸蛋白酶具有选择性，口服给药后其暴露水平高于类似的苯甲脒和苯甲脒类似物。化合物33在犬类动静脉血栓形成模型中有效。