Inhibition of matrix metalloproteinases by N-carboxyalkyl peptides.
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.
Chapman
K T
KT
Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, New Jersey 07065-0900.
Kopka
I E
IE
Durette
P L
PL
Esser
C K
CK
Lanza
T J
TJ
Izquierdo-Martin
M
M
Niedzwiecki
L
L
Chang
B
B
Harrison
R K
RK
Kuo
D W
DW
D000595:Amino Acid Sequence; D000818:Animals; D001769:Blood; D017364:Collagenases / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004355:Drug Stability; D005109:Extracellular Matrix / Q000201:enzymology*; D005347:Fibroblasts / Q000201:enzymology; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011817:Rabbits; D013329:Structure-Activity Relationship
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C085083:N-(1-carboxyethyl)-alpha-(2-phenylethyl)glycyl-leucine, N-phenylamide; D017364:Collagenases; D018093:Gelatinases; D008666:Metalloendopeptidases; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2