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 |
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Hauptverfasser: | , , , , , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Online-Zugang: | Volltext |
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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. |
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ISSN: | 0022-2623 1520-4804 |
DOI: | 10.1021/jm970493r |