Design, synthesis, and biological activity of novel factor Xa inhibitors: 4-aryloxy substituents of 2,6-diphenoxypyridines |
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Authors: | Ng Howard P Buckman Brad O Eagen Keith A Guilford William J Kochanny Monica J Mohan Raju Shaw Kenneth J Wu Shung C Lentz Dao Liang Amy Trinh Lan Ho Elena Smith David Subramanyam Babu Vergona Ron Walters Janette White Kathy A Sullivan Mark E Morrissey Michael M Phillips Gary B |
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Affiliation: | Pharmaceuticals Research, Berlex Biosciences, 15049 San Pablo Avenue, PO Box 4099, Richmond, CA 94804-0099, USA. |
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Abstract: | A novel series of triaryloxypyridines have been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. Inhibitor 5e has a K(I) against factor Xa of 0.12nM and is greater than 8000- and 2000-fold selective over two related serine proteases, thrombin and trypsin, respectively. The 4-position of the central pyridine has been identified as a site that tolerates various substitutions without deleterious effects on potency and selectivity. This suggests that the 4-position of the pyridine ring is an ideal site for chemical modifications to identify inhibitors with improved pharmacokinetic characteristics. This investigation has resulted in inhibitor 5d, which has an oral availability of 6% in dogs. The synthesis, in vitro activity, and in vivo profile of this class of inhibitors is outlined. |
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