Phosphonamidate inhibitors of human neutrophil collagenase.
A series of phosphonamidates has been synthesized and shown to inhibit human neutrophil collagenase. The compounds all have sequences patterned after the cleavage site in the alpha 1(I) chain of type I collagen, except that the carbonyl group of the Gly residue in subsite P1 has been replaced by a P(= O)(OH) group (abbreviated GlyP). As the central GlyP-Leu unit is lengthened in the N- and C-terminal directions, in accordance with the cleavage sequence found in collagen, inhibition is systematically improved. The best inhibitor is Cbz-GlyP-Leu-Ala-Gly, which inhibits competitively with a KI value of 14 microM. These phosphonamidates are thought to be acting as transition-state analogues.
D001667:Binding, Competitive; D006801:Humans; D007700:Kinetics; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors / Q000097:blood*; D009504:Neutrophils / Q000201:enzymology*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D009943:Organophosphorus Compounds; D003012:Microbial Collagenase