5-Heteroatom substituted pyrazoles as canine COX-2 inhibitors. Part III: molecular modeling studies on binding contribution of 1-(5-methylsulfonyl)pyrid-2-yl and 4-nitrile.
The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs.
Sakya
Subas M
SM
Veterinary Medicine Research and Development, Pfizer Inc., Groton, CT 06340, USA. subas.m.sakya@pfizer.com
Hou
Xinjun
X
Minich
Martha L
ML
Rast
Bryson
B
Shavnya
Andrei
A
DeMello
Kristin M L
KM
Cheng
Hengmiao
H
Li
Jin
J
Jaynes
Burton H
BH
Mann
Donald W
DW
Petras
Carol F
CF
Seibel
Scott B
SB
Haven
Michelle L
ML
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D000068579:Celecoxib; D051545:Cyclooxygenase 1 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*
C518769:1-(5-methylsulfonyl)pyrid-2-yl; C518770:1-(5-methylsulfonyl)pyrid-4-nitrile; D052246:Cyclooxygenase 2 Inhibitors; D007202:Indicators and Reagents; D009570:Nitriles; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D013450:Sulfones; D051545:Cyclooxygenase 1; D000068579:Celecoxib