Beta-aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme.
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.
Kottirsch
Georg
G
Preclinical Research Novartis Pharma AG, CH-4002 Basel, Switzerland.
Koch
Guido
G
Feifel
Roland
R
Neumann
Ulf
U
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C455823:N(4)-(2,2-dimethyl-1-methylcarbamoylpropyl)-N(1)-hydroxy-2-hydroxymethyl-3-(4-methoxyphenyl)succinamide; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606464:Adam17 protein, rat