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

Author(s): Carol K. Wada.

Journal Name: Current Topics in Medicinal Chemistry

Volume 4 , Issue 12 , 2004

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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

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Article Details

VOLUME: 4
ISSUE: 12
Year: 2004
Page: [1255 - 1267]
Pages: 13
DOI: 10.2174/1568026043388015
Price: $58

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