INHIBITION OF MATRIX METALLOPROTEINASES BY N-CARBOXYALKYL PEPTIDES

An extensive study of the requirements for effective binding of N-carb oxyalkyl peptides to human stromelysin, collagenase, and to a lesser e xtent, gelatinase A has been investigated. These efforts afforded inhi bitors generally in the 100-400 nM range for these matrix metalloprote inases. The most significant increase in potency was obtained with the introduction of a beta-phenylethyl group at the P-1' position, sugges ting a small hydrophobic channel into the S-1' subsite of stromelysin. One particular compound, xyethyl]-alpha(S)-(2-phenylethyl)glycyl-L-le ucine, N-phenylamide (79a), is relatively selective for rabbit stromel ysin with a K-i = 6.5 nM and may prove useful for elucidating the role of endogenously-produced stromelysin in lapine models of tissue degra dation.