从苗头化合物到先导化合物的两种凝血因子IXa抑制剂的快速研发。

Rapid development of two factor IXa inhibitors from hit to lead.

作者信息

Parker Dann L, Walsh Shawn, Li Bing, Kim Esther, Sharipour Aurash, Smith Cameron, Chen Yi-Heng, Berger Richard, Harper Bart, Zhang Ting, Park Min, Shu Min, Wu Jane, Xu Jiayi, Dewnani Sunita, Sherer Edward C, Hruza Alan, Reichert Paul, Geissler Wayne, Sonatore Lisa, Ellsworth Kenneth, Balkovec James, Greenlee William, Wood Harold B

机构信息

Department of Medicinal Chemistry, Merck Research Laboratories, Merck and Co., Inc, PO Box 2000, E. Lincoln Ave., Rahway, NJ 07016, USA.

出版信息

Bioorg Med Chem Lett. 2015 Jun 1;25(11):2321-5. doi: 10.1016/j.bmcl.2015.04.025. Epub 2015 Apr 13.

DOI:10.1016/j.bmcl.2015.04.025

PMID:25937013

Abstract

Two high-throughput screening hits were investigated for SAR against human factor IXa. Both hits feature a benzamide linked to a [6-5]-heteroaryl via an alkyl amine. In the case where this system is a benzimidazolyl-ethyl amine the binding potency for the hit was improved >500-fold, from 9 μM to 0.016 μM. For the other hit, which contains a tetrahydropyrido-indazole amine, potency was improved 20-fold, from 2 μM to 0.09 μM. X-ray crystal structures were obtained for an example of each class which improved understanding of the binding, and will enable further drug discovery efforts.

摘要

对两种高通量筛选命中化合物进行了针对人凝血因子IXa的构效关系研究。这两种命中化合物均具有通过烷基胺连接到[6-5]杂芳基的苯甲酰胺结构。当该体系为苯并咪唑基乙胺时，命中化合物的结合效力提高了500倍以上，从9 μM提高到0.016 μM。对于另一种含有四氢吡啶并吲唑胺的命中化合物，效力提高了20倍，从2 μM提高到0.09 μM。获得了每类化合物的一个实例的X射线晶体结构，这有助于更好地理解结合情况，并将推动进一步的药物发现工作。