Potent, selective, orally bioavailable inhibitors of tumor necrosis factor-α converting enzyme (TACE):: Discovery of indole, benzofuran, imidazopyridine and pyrazolopyridine P1′ substituents

Potent and selective inhibitors of tumor necrosis factor-a converting enzyme ( TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC50 value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F% > 90%) in rat n-in-1 PK studies. (C) 2008 Elsevier Ltd. All rights reserved.