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Rapid development of two factor IXa inhibitors from hit to lead

2015; Elsevier BV; Volume: 25; Issue: 11 Linguagem: Inglês

10.1016/j.bmcl.2015.04.025

1464-3405

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

Chemical Synthesis and Analysis

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.