Synthesis and pharmacological evaluation of <Emphasis Type="Italic">m</Emphasis>-terphenyl amines as cyclooxygenase inhibitors |
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| Authors: | John D Bauer Michael S Foster Jeffrey D Hugdahl Kristi L Burns Sheldon W May Stanley H Pollock Horace G Cutler Stephen J Cutler |
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| Institution: | (1) College of Pharmacy and Health Sciences, Mercer University, Atlanta, GA 30341, USA;(2) School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332, USA;(3) Department of Chemistry, College of Liberal Arts, Mercer University, 1400 Coleman Avenue, Macon, GA 31207, USA;(4) Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, USA |
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| Abstract: | A series of m-terphenyl amines was synthesized and evaluated as a novel class of cyclooxygenase (COX) inhibitors. Structure–activity relationships
(SAR) were investigated by functional group modification at the para-position of the C-1′ and C-2′ phenyl substituents on the central aromatic ring. Anilines 6a, b, d, and h demonstrated nonselective inhibition of COX-1 and -2 in human whole blood. Compounds 6c and e demonstrated preferential inhibition of the COX-2 isozyme at 10 μM. Molecules 6f, i, and j inhibited only COX-1, and the disubstituted ethoxy derivative (6g) was inactive as a COX inhibitor (≤ 100 μM). Molecular docking studies of these compounds indicate that the COX-1 binding
site amino acid Ile523 anchors the m-terphenyl system statically within the enzyme’s active site, while the slightly smaller amino acid Val523 in COX-2 allows the ligand to “roll,” fashioning several acceptable conformers. |
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