Design, Synthesis, and Activity of a Novel Series of Factor Xa Inhibitors: Optimization of Arylamidine Groups 1, 2

…, HP Ng, M Pinkerton, B Subramanyam…

Index: Phillips, Gary; Guilford, William J.; Buckman, Brad O.; Davey, David D.; Eagen, Keith A.; Koovakkat, Sunil; Liang, Amy; McCarrick, Meg; Mohan, Raju; Ng, Howard P.; Pinkerton, Michael; Subramanyam, Babu; Ho, Elena; Trinh, Lan; Whitlow, Marc; Wu, Shung; Xu, Wei; Morrissey, Michael M. Journal of Medicinal Chemistry, 2002 , vol. 45, # 12 p. 2484 - 2493

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Citation Number: 19

Abstract

A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to ...