Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution

M L Curtin; R B Garland; S K Davidsen; P A Marcotte; D H Albert; T J Magoc; C Hutchins

doi:10.1016/s0960-894x(98)00255-8

Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution

Bioorg Med Chem Lett. 1998 Jun 16;8(12):1443-8. doi: 10.1016/s0960-894x(98)00255-8.

Authors

M L Curtin¹, R B Garland, S K Davidsen, P A Marcotte, D H Albert, T J Magoc, C Hutchins

Affiliation

¹ Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.

PMID: 9873367
DOI: 10.1016/s0960-894x(98)00255-8

Abstract

A series of P1 C alpha gem-disubstituted succinamide hydroxamate matrix metalloproteinase inhibitors were prepared stereoselectively and evaluated in vitro for their ability to inhibit MMP-1, MMP-2, and MMP-3. It was found that while methyl/allyl substitution as in 2 and 18 provided compounds that were broad spectrum inhibitors and nearly equipotent with parent inhibitor 1, a larger group such as bis-allyl as in 13 or gem-cyclopentyl as in 14 significantly reduced enzyme inhibition.

MeSH terms

Animals
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacokinetics
Hydroxamic Acids / pharmacology*
Metalloendopeptidases / antagonists & inhibitors*
Models, Molecular
Molecular Structure
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacokinetics
Protease Inhibitors / pharmacology*
Rats

Substances

Hydroxamic Acids
Protease Inhibitors
Metalloendopeptidases