The evolution of the matrix metalloproteinase inhibitor drug discovery program at abbott laboratories.

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.

• Authors: Carol K Wada
• Journal: Current topics in medicinal chemistry (Curr Top Med Chem) Vol. 4 Issue 12 Pg. 1255-67 ( 2004) ISSN: 1568-0266 [Print] United Arab Emirates
• PMID: 15320725 (Publication Type: Journal Article, Review)

Chemical References

• Matrix Metalloproteinase Inhibitors
• Protease Inhibitors

Topics

• Animals
• Drug Design
• Drug Industry
• Humans
• Magnetic Resonance Spectroscopy
• Matrix Metalloproteinase Inhibitors
• Protease Inhibitors (chemical synthesis, pharmacology)
• Structure-Activity Relationship