Macrocyclic hydroxamate inhibitors of matrix metalloproteinases and TNF-alpha production

R J Cherney; L Wang; D T Meyer; C B Xue; E C Arner; R A Copeland; M B Covington; K D Hardman; Z R Wasserman; B D Jaffee; C P Decicco

doi:10.1016/s0960-894x(99)00178-x

Macrocyclic hydroxamate inhibitors of matrix metalloproteinases and TNF-alpha production

Bioorg Med Chem Lett. 1999 May 3;9(9):1279-84. doi: 10.1016/s0960-894x(99)00178-x.

Authors

R J Cherney¹, L Wang, D T Meyer, C B Xue, E C Arner, R A Copeland, M B Covington, K D Hardman, Z R Wasserman, B D Jaffee, C P Decicco

Affiliation

¹ The DuPont Pharmaceutical Co., Experimental Station, Wilmington, DE 19880-0500, USA.

PMID: 10340614
DOI: 10.1016/s0960-894x(99)00178-x

Abstract

Several macrocyclic, hydroxamate derivatives were synthesized and evaluated as inhibitors of matrix metalloproteinases (MMPs) and tumour necrosis factor-alpha (TNF-alpha) production. These macrocycles are anti-succinate based inhibitors linked from P1 to P2'. A variety of functionality was installed at the P1-P2' linkage, which gave inhibitors that displayed excellent MMP inhibition and good TNF-alpha suppression.

MeSH terms

Crystallography, X-Ray
Humans
Hydroxamic Acids / chemistry*
Inhibitory Concentration 50
Kinetics
Lipopolysaccharides / metabolism
Matrix Metalloproteinase 1
Matrix Metalloproteinase 9
Matrix Metalloproteinase Inhibitors
Metalloendopeptidases / antagonists & inhibitors*
Metalloendopeptidases / classification
Models, Chemical
Models, Molecular
Tumor Necrosis Factor-alpha / antagonists & inhibitors*

Substances

Hydroxamic Acids
Lipopolysaccharides
Matrix Metalloproteinase Inhibitors
Tumor Necrosis Factor-alpha
Metalloendopeptidases
Matrix Metalloproteinase 9
Matrix Metalloproteinase 1