Design, synthesis, and biological evaluation of potent thiazine- and thiazepine-based matrix metalloproteinase inhibitors.
The synthesis and enzyme inhibition data for a series of thiazine- and thiazepine-based matrix metalloproteinase (MMP) inhibitors are described. The thiazine- and thiazepine-based inhibitors were discovered by optimization of hetererocyclic sulfonamide-based inhibitors. The most potent series of inhibitors was obtained by modification of the amino acid D-penicillamine. This amino acid provides a gem-dimethyl group on the thiazine or thiazepine ring which has a dramatic effect on the in vitro potency of this series. In particular, the sulfide 4a and the sulfone 5a were potent, broad-spectrum inhibitors of the MMPs with IC(50)'s against MMP-1 of 0.8 and 1.9 nM, respectively. The binding mode of this novel thiazepine-based series of MMP inhibitors was established based on X-ray crystallography of the complex of stromelysin and 4a.
Almstead
N G
NG
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, Ohio 45040, USA.
Bradley
R S
RS
Pikul
S
S
De
B
B
Natchus
M G
MG
Taiwo
Y O
YO
Gu
F
F
Williams
L E
LE
Hynd
B A
BA
Janusz
M J
MJ
Dunaway
C M
CM
Mieling
G E
GE
D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000138:chemical synthesis* / Q000737:chemistry; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry
D003499:Cyclic S-Oxides; D004791:Enzyme Inhibitors; C401383:N-hydroxy-4-((4--methoxyphenyl)sulfonyl)-2,2-dimethylhexahydro-1,4-thiazepine-3-carboxamide 1,1-dioxide; C401382:N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,2-dimethylhexahydro-1,4-thiazepine-3-carboxamide; D013841:Thiazepines; D013843:Thiazines; D008666:Metalloendopeptidases