NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability

…, M Michaelides, SK Davidsen, SW Fesik

Index: Hajduk, Philip J.; Shuker, Suzanne B.; Nettesheim, David G.; Craig, Richard; Augeri, David J.; Betebenner, David; Albert, Daniel H.; Guo, Yan; Meadows, Robert P.; Xu, Lianhong; Michaelides, Michael; Davidsen, Steven K.; Fesik, Stephen W. Journal of Medicinal Chemistry, 2002 , vol. 45, # 26 p. 5628 - 5639

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Citation Number: 68

Abstract

The NMR-based discovery of biaryl hydroxamate inhibitors of the matrix metalloproteinase stromelysin (MMP-3) has been previously described (Hajduk et al. J. Am. Chem. Soc. 1997, 119, 5818-5827). While potent in vitro, these inhibitors exhibited no in vivo activity due, at least in part, to the poor pharmacokinetic properties of the alkylhydroxamate moiety. To circumvent this liability, NMR-based screening was implemented to identify alternative ...