Development of a novel tricyclic class of potent and selective FIXa inhibitors. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Meng, Dongfang; Andre, Patrick; Bateman, Thomas J.; Berger, Richard; Chen, Yi-Heng; Desai, Kunal; Dewnani, Sunita; Ellsworth, Kenneth; Feng, Daming; Geissler, Wayne M.; Guo, Liangqin; Hruza, Alan; Jian, Tianying; Li, Hong; Metzger, Joe; Parker, Dann L.; Reichert, Paul; Sherer, Edward C.; Smith, Cameron J.; Sonatore, Lisa M.; Tschirret-Guth, Richard; Wu, Jane; Xu, Jiayi; Zhang, Ting; Campeau, Louis-Charles; Orr, Robert; Poirier, Marc; McCabe-Dunn, Jamie; Araki, Kazuto; Nishimura, Teruyuki; Sakurada, Isao; Hirabayashi, Tomokazu; Wood, Harold B.;
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 22(2015)
• Page Start: 5437
• Page End: 5443
• Publication Date: 2015-11-15
• Subjects: Benzimidazole -- Quninazolinone -- FIXa inhibitor -- TGA -- Structure based drug design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.07.078
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.