Discovery of a Novel, Selective, and Orally Bioavailable Class of Thrombin Inhibitors Incorporating Aminopyridyl Moieties at the P1 Position

A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (K i 0.8−12 nM), 300−1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (...

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Veröffentlicht in:Journal of medicinal chemistry 1997-11, Vol.40 (23), p.3726-3733
Hauptverfasser: Feng, Dong-Mei, Gardell, Stephen J, Lewis, S. Dale, Bock, Mark G, Chen, Zhongguo, Freidinger, Roger M, Naylor-Olsen, Adel M, Ramjit, Harri G, Woltmann, Richard, Baskin, Elizabeth P, Lynch, Joseph J, Lucas, Robert, Shafer, Jules A, Dancheck, Kimberley B, Chen, I-Wu, Mao, Shi-Shan, Krueger, Julie A, Hare, Timothy R, Mulichak, Anne M, Vacca, Joseph P
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Sprache:eng
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Zusammenfassung:A novel class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position has been discovered. Four of these thrombin inhibitors (13b,c,e and 14d) showed nanomolar potency (K i 0.8−12 nM), 300−1500-fold selectivity for thrombin compared with trypsin, and good oral bioavailability (F = 40−76%) in rats or dogs. The neutral P1 was expected to increase metabolic stability and oral absorption. Identification of this novel aminopyridyl group at P1 was a key step in our search for a clinical candidate.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm970493r