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

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

PMID: 12477346 · DOI:10.1021/jm020160g

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.

MeSH Terms (13)

Animals Biological Availability Catalytic Domain Hydroxamic Acids Magnetic Resonance Spectroscopy Matrix Metalloproteinase 3 Matrix Metalloproteinase Inhibitors Models, Molecular Naphthalenes Protease Inhibitors Protein Binding Rats Structure-Activity Relationship

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