title: 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.
abstract: 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.
authors.affiliation: Veterinary Medicine Research and Development, Pfizer Inc., Groton, CT 06340, USA. subas.m.sakya@pfizer.com
authors.forename: Subas M
authors.initials: SM
authors.lastname: Sakya
authors.forename: Xinjun
authors.initials: X
authors.lastname: Hou
authors.forename: Martha L
authors.initials: ML
authors.lastname: Minich
authors.forename: Bryson
authors.initials: B
authors.lastname: Rast
authors.forename: Andrei
authors.initials: A
authors.lastname: Shavnya
authors.forename: Kristin M L
authors.initials: KM
authors.lastname: DeMello
authors.forename: Hengmiao
authors.initials: H
authors.lastname: Cheng
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.forename: Burton H
authors.initials: BH
authors.lastname: Jaynes
authors.forename: Donald W
authors.initials: DW
authors.lastname: Mann
authors.forename: Carol F
authors.initials: CF
authors.lastname: Petras
authors.forename: Scott B
authors.initials: SB
authors.lastname: Seibel
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Haven
mesh_terms: 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*
chemical_list: 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