Search

The matrix metalloproteinase stromelysin-1 (MMP-3) is inhibited more strongly by peptidyl phosphinic acid 7 than by its corresponding phosphonamidate and phosphonate analogs. Extending a benzyl group at P′ 1 to a phenylethyl group in 8 further increases the potency (K i = 1.4 nM). Enhanced potency with an extended substituent into the P 3 region was observed.

Aroyl and arylacyl aminoalkyl substitutents at the P 1 position of N -carboxyalkyl dipeptides were found to enhance potency and selectivity for stromelysin-1 (MMP-3). In particular, the phthalimidobutyl and phenylpropanoylaminopropyl groups offered inhibitors of MMP-3 with K i 's of ∼ 10nM.

A series of N-carboxyalkyl dipeptides were synthesized to evaluate their inhibitory activities against human stromelysin-1(MMP-3), collagenase(MMP-1), and gelatinase-A(MMP-2). Structures with a homophenylalanine residue at P1′ substituted at the para position with small alkyl groups are potent inhibitors of (MMP-3) and (MMP-2) (Ki′ s 2–40 nM), but weak inhibitors of (MMP-1).

A series of N-carboxyalkyl peptides were prepared to test their inhibitory activity against human stromelysin (MMP-3), collagenase (MMP-1), and gelatinase A (MMP-2). Linear alkyl and ω-aminoalkyl residues were employed as replacements for a phenethyl group yielding inhibitors with in vitro activities comparable to their corresponding aromatic analogs.

A series of phosphinic acid-containing peptide inhibitors of human stromelysin-1 (MMP-3) were prepared. The P1 through P3 subsites were varied in a systematic manner on analogs possessing an invariant P1′-P3′ segment. The in vitro activity of these compounds as inhibitors of stromelysin and collagenase is discussed.

An extensive study of the requirements for effective binding of N-carboxyalkyl peptides to human stromelysin, collagenase, and to a lesser extent, gelatinase A has been investigated. These efforts afforded inhibitors generally in the 100-400 nM range for these matrix metalloproteinases. The most significant increase in potency was obtained with the introduction of a beta-phenylethyl group at the P1' position, suggesting a small hydrophobic channel into the S1' subsite of stromelysin. One particular compound, N-[1(R)-carboxyethyl]-alpha(S)-(2-phenylethyl)glycyl-L-leucine,N- phenylamide (79a), is relatively selective for rabbit stromelysin with a K(i) = 6.5 nM and may prove useful for elucidating the role of endogenously-produced stromelysin in lapine models of tissue degradation.