Beta-aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme

Georg Kottirsch; Guido Koch; Roland Feifel; Ulf Neumann

doi:10.1021/jm0110993

Beta-aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme

J Med Chem. 2002 May 23;45(11):2289-93. doi: 10.1021/jm0110993.

Authors

Georg Kottirsch¹, Guido Koch, Roland Feifel, Ulf Neumann

Affiliation

¹ Preclinical Research Novartis Pharma AG, CH-4002 Basel, Switzerland.

PMID: 12014967
DOI: 10.1021/jm0110993

Abstract

Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFalpha levels with an ED50 of 1 mg/kg.

MeSH terms

ADAM Proteins
ADAM17 Protein
Administration, Oral
Animals
Cells, Cultured
Humans
Hydroxamic Acids / chemical synthesis*
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology
Leukocytes, Mononuclear / metabolism
Male
Matrix Metalloproteinase Inhibitors*
Metalloendopeptidases / antagonists & inhibitors*
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism*

Substances

Hydroxamic Acids
Matrix Metalloproteinase Inhibitors
N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide
Protease Inhibitors
Tumor Necrosis Factor-alpha
ADAM Proteins
Metalloendopeptidases
ADAM17 Protein
ADAM17 protein, human
Adam17 protein, rat