[NMR paper] NMR-based modification of matrix metalloproteinase inhibitors with improved bioavaila

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NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability.

Related Articles NMR-based modification of matrix metalloproteinase inhibitors with improved bioavailability.

J Med Chem. 2002 Dec 19;45(26):5628-39

Authors: Hajduk PJ, Shuker SB, Nettesheim DG, Craig R, Augeri DJ, Betebenner D, Albert DH, Guo Y, Meadows RP, Xu L, Michaelides M, Davidsen SK, Fesik SW

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 zinc-chelating groups. Using this technique, 1-naphthyl hydroxamate was found to bind tightly to the protein (K(D) = 50 microM) and was identified as a candidate for incorporation into the lead series. On the basis of NMR-derived structural information, the naphthyl hydroxamate and biaryl fragments were linked together to yield inhibitors of this enzyme that exhibited improved bioavailability. These studies demonstrate that the NMR-based screening of fragments can be effectively applied to improve the physicochemical or pharmacokinetic profile of lead compounds.

PMID: 12477346 [PubMed - indexed for MEDLINE]



Source: PubMed