Phosphonamidate inhibitors of human neutrophil collagenase

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Abstract
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site in the .alpha.1 (1) chain of type I collagen, except that the carbonyl group of the Gly residue in subsite P1 has been replaced by a P (.dbd. 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 K1 value of 14 .mu.M. These phosphonamidates are thought to be acting as transition-state analogues.