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The Evolution of the Matrix Metalloproteinase Inhibitor Drug Discovery Program at Abbott Laboratories

[ Vol. 4 , Issue. 12 ]

Author(s):

Carol K. Wada   Pages 1255 - 1267 ( 13 )

Abstract:


Matrix metalloproteinases (MMPs) have been implicated in several pathologies. At Abbott Laboratories, the matrix metalloproteinases inhibitor drug discovery program has focused on the discovery of a potent, selective, orally bioavailable MMP inhibitor for the treatment of cancer. The program evolved from early succinate-based inhibitors to utilizing in-house technology such as SAR by NMR to develop a novel class of biaryl hydroxamate MMP inhibitors. The metabolic instability of the biaryl hydroxamates led to the discovery of a new class of N-formylhydroxylamine (retrohydroxamate) biaryl ethers, exemplified by ABT-770 ( 16). Toxicity issues with this pre-clinical candidate led to the discovery of another novel class of retrohydroxamate MMP inhibitors, the phenoxyphenyl sulfones such as ABT-518 ( 19j). ABT-518 is a potent, orally bioavailable, selective inhibitor of MMP-2 and 9 over MMP-1 that has been evaluated in Phase I clinical trials in cancer patients.

Keywords:

mmps, mmp inhibitor, biaryl hydroxamate, n-formylhydroxylamine, retrohydroxamate

Affiliation:

Abbott Laboratories, Dept. R47J, Bldg. AP10, 100 Abbott Park Rd., Abbott Park, IL 60064-6100, USA



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