Synthesis and pharmacological evaluation of m-terphenyl amines as cyclooxygenase inhibitors

Autor: Michael S. Foster, John D. Bauer, Sheldon W. May, Stephen J. Cutler, Stanley H. Pollock, Horace G. Cutler, Kristi L. Burns, Jeffrey D. Hugdahl
Rok vydání: 2007
Předmět:
Zdroj: Medicinal Chemistry Research. 16:119-129
ISSN: 1554-8120
1054-2523
DOI: 10.1007/s00044-007-9015-x
Popis: 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.
Databáze: OpenAIRE
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