Synthesis of novel modified dipeptide inhibitors of human collagenase: beta-mercapto carboxylic acid derivatives.
Beszant B, Bird J, Gaster LM, Harper GP, Hughes I, Karran EH, Markwell RE, Miles-Williams AJ, Smith SA.
The synthesis of a series of thiol-containing, modified dipeptide inhibitors (8) of human collagenase, which incorporate various carboxylic acid derivatives at the presumed P1 position, beta to the thiol group, is described. The compounds were evaluated, in vitro, for their ability to inhibit the degradation of rat skin type 1 collagen by purified human lung fibroblast collagenase, and structure-activity relationship studies are described. Optimum potency (IC50 values in the nanomolar range) was achieved by incorporating methyl (compounds 43a, 56a, and 57ab) or benzyl esters (44a) at the P1 position. Small amides were also accommodated (e.g. primary amide 47a), but in general, increasing the size of the P1 amide substituent lowered potency. PheNHMe, TrpNHMe, and Tyr(Me)NHMe substituents were found to be approximately equipotent P2'-residues. The results of testing all four diastereoisomers 56a-d of the compound with (S)-TrpNHMe at the P2' position indicated that the S,S,S diastereoisomer 56a possessed highest potency (IC50 2.5 nM) and that the second most potent diastereoisomer was 56d (IC50 12 nM) with the R,R,S configuration. It appeared that the orientation of the P1' and the thiol-bearing centers to each other is a more critical influence on potency than any absolute stereochemical requirements. It is suggested that the high potency of the beta-mercapto carboxylic acid derivatives may be a consequence of bidentate coordination of the thiol and carbonyl groups to the active-site zinc ion in the collagenase enzyme.