Design and synthesis of aminophenol-based factor Xa inhibitors |
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Authors: | Wu Shung Guilford William J Chou Yuo-Ling Griedel Brian D Liang Amy Sakata Steve Shaw Kenneth J Trinh Lan Xu Wei Zhao Zuchun Morrissey Michael M |
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Affiliation: | Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, 94804-0099, Richmond, CA, USA |
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Abstract: | A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure. |
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