- Discovery of nonbenzamidine factor VIIa inhibitors using a biaryl acid scaffold
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In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
- Bolton, Scott A.,Sutton, James C.,Anumula, Rushith,Bisacchi, Gregory S.,Jacobson, Bruce,Slusarchyk, William A.,Treuner, Uwe D.,Wu, Shung C.,Zhao, Guohua,Pi, Zulan,Sheriff, Steven,Smirk, Rebecca A.,Bisaha, Sharon,Cheney, Daniel L.,Wei, Anzhi,Schumacher, William A.,Hartl, Karen S.,Liu, Eddie,Zahler, Robert,Seiler, Steven M.
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p. 5239 - 5243
(2013/09/12)
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- Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores
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Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF·FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF·FVIIa inhibitors. Parallel synthesis coupled with structure-based drug design allowed us to explore the S2 pocket of the enzyme active site. A number of compounds with IC50 value of 10 nM were synthesized. The X-ray crystal structures of some of these compounds complexed with TF·FVIIa were determined and results were applied to design the next round of inhibitors. All the potent inhibitors were tested for inhibition against a panel of related enzymes and selectivity of 17,600 over thrombin, 450 over trypsin, 685 over FXa, and 76 over plasmin was achieved. Two groups, vinyl 36b and 2-furan 36ab, were identified as the optimum binding substituents on the phenyl ring in the S2 pocket. Compounds with these two substituents are the most potent compounds in this series with good selectivity over related serine proteases. These compounds will be further explored for structure-activity relationship.
- Kotian, Pravin L.,Krishnan, Raman,Rowland, Scott,El-Kattan, Yahya,Saini, Surendra K.,Upshaw, Ramanda,Bantia, Shanta,Arnold, Shane,Sudhakar Babu,Chand, Pooran
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experimental part
p. 3934 - 3958
(2009/10/02)
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- Tetrahydroquinoline derivatives as antithrombotic agents
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This invention relates generally to tetracyclic tetrahydroquinoline compounds, and analogues thereof, and pharmaceutically acceptable salt forms thereof, which are selective inhibitors of serine protease enzymes, especially factor VIIa; pharmaceutical compositions containing the same; and methods of using the same as anticoagulant agents for modulation of the coagulation cascade.
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