...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Journal of Medicinal Chemistry >Discovery of 1-(3-(aminomethyl)phenyl)-N-3-fluoro-2'-(methylsulfonyl)-(1,1'-biphenyl)-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.
【24h】

Discovery of 1-(3-(aminomethyl)phenyl)-N-3-fluoro-2'-(methylsulfonyl)-(1,1'-biphenyl)-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide (DPC423), a highly potent, selective, and orally bioavailable inhibitor of blood coagulation factor Xa.

机译：1-（3-（氨基甲基）苯基）-N-3-氟-2'-（甲基磺酰基）-（1,1'-联苯）-4-基）-3-（三氟甲基）-1H-吡唑-的发现5-羧酰胺（DPC423），一种高效，选择性和口服生物利用度的凝血因子Xa抑制剂。

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Factor Xa (fXa) plays a critical role in the coagulation cascade, serving as the point of convergence of the intrinsic and extrinsic pathways. Together with nonenzymatic cofactor Va and Ca2+ on the phospholipid surface of platelets or endothelial cells, factor Xa forms the prothrombinase complex, which is responsible for the proteolysis of prothrombin to catalytically active thrombin. Thrombin, in turn, catalyzes the cleavage of fibrinogen to fibrin, thus initiating a process that ultimately leads to clot formation. Recently, we reported on a series of isoxazoline and isoxazole monobasic noncovalent inhibitors of factor Xa which show good potency in animal models of thrombosis. In this paper, we wish to report on the optimization of the heterocyclic core, which ultimately led to the discovery of a novel pyrazole SN429 (2b; fXa K(i) = 13 pM). We also report on our efforts to improve the oral bioavailability and pharmacokinetic profile of this series while maintaining subnanomolar potency and in vitro selectivity. This was achieved by replacing the highly basic benzamidine P1 with a less basic benzylamine moiety. Further optimization of the pyrazole core substitution and the biphenyl P4 culminated in the discovery of DPC423 (17h), a highly potent, selective, and orally active factor Xa inhibitor which was chosen for clinical development.
机译：Xa因子（fXa）在凝血级联中起关键作用，是内在和外在途径的汇合点。 Xa因子与血小板或内皮细胞磷脂表面上的非酶辅因子Va和Ca2 +一起形成凝血酶原酶复合物，该复合物负责凝血酶原的蛋白水解成催化活性的凝血酶。凝血酶继而催化血纤蛋白原裂解为血纤蛋白，从而启动了最终导致血凝块形成的过程。最近，我们报道了一系列Xa因子的异恶唑啉和异恶唑一元非共价抑制剂，它们在血栓形成的动物模型中显示出良好的效力。在本文中，我们希望报告杂环核心的优化，这最终导致发现了新型吡唑SN429（2b; fXa K（i）= 13 pM）。我们还报告了我们在改善该系列产品的口服生物利用度和药代动力学方面所做的努力，同时保持了亚纳摩尔效价和体外选择性。这是通过用碱性较低的苄胺部分取代高碱性的苯甲idine P1来实现的。吡唑核心取代和联苯P4的进一步优化最终导致了DPC423的发现（17h），DPC423是一种高效，选择性和口服活性因子Xa抑制剂，已被选择用于临床开发。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号