The development of new carboxylic acid-based MMP inhibitors derived from a cyclohexylglycine scaffold.
A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7.
Tullis
J S
JS
Procter and Gamble Pharmaceuticals, Health Care Research Center, 8700Mason-Montgomery Rd, Mason, OH 45040, USA.
Laufersweiler
M J
MJ
VanRens
J C
JC
Natchus
M G
MG
Bookland
R G
RG
Almstead
N G
NG
Pikul
S
S
De
B
B
Hsieh
L C
LC
Janusz
M J
MJ
Branch
T M
TM
Peng
S X
SX
Jin
Y Y
YY
Hudlicky
T
T
Oppong
K
K
D000818:Animals; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D017364:Collagenases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; C507083:Mmp13 protein, rat; D019278:Matrix Metalloproteinase 3; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D005998:Glycine