Design and synthetic considerations of matrix metalloproteinase inhibitors.

Abstract:

:Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.

journal_name

Ann N Y Acad Sci

authors

Skotnicki JS,Zask A,Nelson FC,Albright JD,Levin JI

doi

10.1111/j.1749-6632.1999.tb07674.x

subject

Has Abstract

pub_date

1999-06-30 00:00:00

pages

61-72

eissn

0077-8923

issn

1749-6632

journal_volume

878

pub_type

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