The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.
Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.
Pratt
L M
LM
British Biotech Pharmaceuticals Limited, Cowley, Oxford.
Beckett
R P
RP
Bellamy
C L
CL
Corkill
D J
DJ
Cossins
J
J
Courtney
P F
PF
Davies
S J
SJ
Davidson
A H
AH
Drummond
A H
AH
Helfrich
K
K
Lewis
C N
CN
Mangan
M
M
Martin
F M
FM
Miller
K
K
Nayee
P
P
Ricketts
M L
ML
Thomas
W
W
Todd
R S
RS
Whittaker
M
M
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002144:Callithrix; D003864:Depression, Chemical; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D006877:Hydroxamic Acids; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D014409:Tumor Necrosis Factor-alpha; D008666:Metalloendopeptidases