Rapid development of two factor IXa inhibitors from hit to lead.
Dann L Parker, Shawn Walsh, Bing Li, Esther Kim, Aurash Sharipour, Cameron Smith, Yi-Heng Chen, Richard Berger, Bart Harper, Ting Zhang, Min Park, Min Shu, Jane Wu, Jiayi Xu, Sunita Dewnani, Edward C Sherer, Alan Hruza, Paul Reichert, Wayne Geissler, Lisa Sonatore, Kenneth Ellsworth, James Balkovec, William Greenlee, Harold B Wood
Bioorganic & medicinal chemistry letters 2015 Jun 1Two 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. Copyright © 2015 Elsevier Ltd. All rights reserved.
Citation
Dann L Parker, Shawn Walsh, Bing Li, Esther Kim, Aurash Sharipour, Cameron Smith, Yi-Heng Chen, Richard Berger, Bart Harper, Ting Zhang, Min Park, Min Shu, Jane Wu, Jiayi Xu, Sunita Dewnani, Edward C Sherer, Alan Hruza, Paul Reichert, Wayne Geissler, Lisa Sonatore, Kenneth Ellsworth, James Balkovec, William Greenlee, Harold B Wood. Rapid development of two factor IXa inhibitors from hit to lead. Bioorganic & medicinal chemistry letters. 2015 Jun 1;25(11):2321-5
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PMID: 25937013
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