Aminoisoquinolines: design and synthesis of an orally active benzamidine isostere for the inhibition of factor Xa

YM Choi-Sledeski, MR Becker, DM Green…

Index: Choi-Sledeski; Becker; Green; Davis; Ewing; Mason; Ly; Spada; Liang; Cheney; Barton; Chu; Brown; Colussi; Bentley; Leadley; Dunwiddie; Pauls Bioorganic and Medicinal Chemistry Letters, 1999 , vol. 9, # 17 p. 2539 - 2544

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Citation Number: 31

Abstract

The design, synthesis and SAR of sulfonamidopyrrolidinone fXA inhibitors incorporating a new benzamidine isostere, namely aminoisoquinolines, is described. These inhibitors have higher Caco-2 cell permeability than comparable benzamidines and attain higher levels of exposure upon oral dosing. The most potent member 14b (fXa Ki= 6 nM) is selective against other serine proteases of interest (> 600 fold).