Heterocycle-based MMP inhibitors with P2' substituents.
Potent and selective inhibition of matrix metalloproteinases was demonstrated for a series of sulfonamide-based hydroxamic acids. The design of the heterocyclic sulfonamides incorporates a six- or seven-member central ring with a P2' substituent that can be modified. Binding interactions of this substituent at the S2' site are believed to contribute to high inhibitory potency against stromelysin, collagenase-3 and gelatinases A and B, and to provide selectivity against collagenase-1 and matrilysin. An X-ray structure of a stromelysin inhibitor complex was obtained to provide insights into the SAR and selectivity trends observed for the series.
Pikul
S
S
Procter and Gamble Pharmaceuticals, Health Care Research Center, Mason, OH 45040, USA. spikul@avalonrx.com
Dunham
K M
KM
Almstead
N G
NG
De
B
B
Natchus
M G
MG
Taiwo
Y O
YO
Williams
L E
LE
Hynd
B A
BA
Hsieh
L C
LC
Janusz
M J
MJ
Gu
F
F
Mieling
G E
GE
D017364:Collagenases; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D046911:Macromolecular Substances; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D046911:Macromolecular Substances; D061965:Matrix Metalloproteinase Inhibitors; D013449:Sulfonamides; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C417249:collagenase 1