Rapid development of two factor IXa inhibitors from hit to lead. Issue 11 (1st June 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 11(2015)
• Page Start: 2321
• Page End: 2325
• Publication Date: 2015-06-01
• Subjects: Factor IXa -- Hit-to-lead -- Structure based drug design -- Parallel synthesis -- Anticoagulant; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.04.025
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.