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

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• 作者：Subas M. Sakya ; Xinjun Hou ; Martha L. Minich ; Bryson Rast ; Andrei Shavnya ; Kristin M.L. DeMello ; Hengmiao Cheng ; Jin Li ; Burton H. Jaynes ; Donald W. Mann ; et al.
• 关键词：Canine ; Cyclooxygenase ; COX-1 ; COX-2 ; Pyrazole ; Heterocyle ; Molecular modelling
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 出版时间：15 February 2007
• 年：2007
• 卷：17
• 期：4
• 页码：1067-1072
• 全文大小：385 K

文摘

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.