INHIBITION OF MATRIX METALLOPROTEINASES BY N-CARBOXYALKYL PEPTIDES

被引:70
作者
CHAPMAN, KT
KOPKA, IE
DURETTE, PL
ESSER, CK
LANZA, TJ
IZQUIERDOMARTIN, M
NIEDZWIECKI, L
CHANG, B
HARRISON, RK
KUO, DW
LIN, TY
STEIN, RL
HAGMANN, WK
机构
[1] MERCK RES LABS, DEPT MED CHEM RES, RAHWAY, NJ 07065 USA
[2] MERCK RES LABS, DEPT ENZYMOL, RAHWAY, NJ 07065 USA
关键词
D O I
10.1021/jm00078a019
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 P-1' position, suggesting a small hydrophobic channel into the S-1' 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.
引用
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页码:4293 / 4301
页数:9
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