SYNTHESIS OF NOVEL N-PHOSPHONOALKYL DIPEPTIDE INHIBITORS OF HUMAN COLLAGENASE

The synthesis of a series of N-phosphonoalkyl dipeptides 6 is describe d. Syntheses were devised that allowed the preparation of single diast ereoisomers and the assignment of stereochemistry. The compounds were evaluated in vitro for their ability to inhibit the degradation of rad iolabeled collagen by purified human lung fibroblast collagenase. Seve ral of the compounds were potent collagenase inhibitors and were at le ast l0-fold more potent than their corresponding N-carboxyalkyl analog ues. Activity was lost when the phosphonic acid group P(O)(OH)(2) was replaced by the phosphinic acid groups P(O)(H)(OH) and P(O)(Me)(OH). A t the P-1 position, (R)- or (S)-allkyl groups, especially ethyl and me thyl (e.g., 12a,b, 52a,b, and 53a,b), or an (R)-phenethyl moiety (55a) conferred high potency (IC50 values in the range 0.23-0.47 mu M). (S) -Stereochemistry was preferred for the P-1(') isobutyl side chain. Str ucture-activity relationships were also investigated at the P-2(') sit e, and interestingly, compounds with basic side chains such as the gua nidine 57a, were equipotent with more lipophilic compounds, such as 52 a. As with other series of collagenase inhibitors, potency was enhance d by introducing bicyclic aromatic P-2(') substituents. The most poten t phosphonic acid of the series was the bicyclic aromatic P-2(') trypt ophan analogue 59a (IC50 0.05 mu M).