Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution.
A series of P1 C alpha gem-disubstituted succinamide hydroxamate matrix metalloproteinase inhibitors were prepared stereoselectively and evaluated in vitro for their ability to inhibit MMP-1, MMP-2, and MMP-3. It was found that while methyl/allyl substitution as in 2 and 18 provided compounds that were broad spectrum inhibitors and nearly equipotent with parent inhibitor 1, a larger group such as bis-allyl as in 13 or gem-cyclopentyl as in 14 significantly reduced enzyme inhibition.
Curtin
M L
ML
Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Garland
R B
RB
Davidsen
S K
SK
Marcotte
P A
PA
Albert
D H
DH
Magoc
T J
TJ
Hutchins
C
C
D000818:Animals; D006877:Hydroxamic Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats
D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D008666:Metalloendopeptidases