Title of article :
Design, Synthesis, and Biological Activity of Novel Factor Xa Inhibitors: 4-Aryloxy Substituents of 2,6-Diphenoxypyridines Original Research Article
Author/Authors :
Howard P. Ng، نويسنده , , Brad O. Buckman، نويسنده , , Keith A. Eagen، نويسنده , , William J. Guilford، نويسنده , , Monica J. Kochanny، نويسنده , , Raju Mohan، نويسنده , , Kenneth J. Shaw، نويسنده , , Shung C. Wu، نويسنده , , Dao Lentz، نويسنده , , Amy Liang، نويسنده , , Lan Trinh، نويسنده , , Elena Ho، نويسنده , , David Smith، نويسنده , , Babu Subramanyam، نويسنده , , Ron Vergona، نويسنده , , Janette Walters، نويسنده , , Kathy A. White، نويسنده , , Mark E. Sullivan، نويسنده , , Michael M. Morrissey، نويسنده , , Gary B. Phillips، نويسنده , , et al.، نويسنده ,
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 KI against factor Xa of 0.12 nM 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.
