Author/Authors :
Chu-Biao Xue، نويسنده , , Xiaohua He، نويسنده , , John Roderick، نويسنده , , Ronald L. Corbett، نويسنده , , James J. -W. Duan، نويسنده , , Ruiqin Liu، نويسنده , , Maryanne B. Covington، نويسنده , , Mingxin Qian، نويسنده , , Maria D. Ribadeneira، نويسنده , , Krishna Vaddi، نويسنده , , David D. Christ، نويسنده , , Robert C. Newton، نويسنده , , James M. Trzaskos، نويسنده , , Ronald L. Magolda، نويسنده , , Ruth R. Wexler، نويسنده , , Carl P. Decicco، نويسنده ,
Abstract :
Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-{[4-(4-quinolinyloxymethyl)anilinyl]carbonyl}-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-α release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide] exhibited an IC50 value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.
