Medicinal Chemistry Research

, Volume 16, Issue 3, pp 119–129

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

  • John D. Bauer
  • Michael S. Foster
  • Jeffrey D. Hugdahl
  • Kristi L. Burns
  • Sheldon W. May
  • Stanley H. Pollock
  • Horace G. Cutler
  • Stephen J. Cutler
Original Research

DOI: 10.1007/s00044-007-9015-x

Cite this article as:
Bauer, J.D., Foster, M.S., Hugdahl, J.D. et al. Med Chem Res (2007) 16: 119. doi:10.1007/s00044-007-9015-x

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.

Copyright information

© Birkha¨user Boston 2007

Authors and Affiliations

  • John D. Bauer
    • 1
  • Michael S. Foster
    • 2
  • Jeffrey D. Hugdahl
    • 3
  • Kristi L. Burns
    • 2
  • Sheldon W. May
    • 2
  • Stanley H. Pollock
    • 1
  • Horace G. Cutler
    • 1
  • Stephen J. Cutler
    • 4
  1. 1.College of Pharmacy and Health SciencesMercer UniversityAtlantaUSA
  2. 2.School of Chemistry and BiochemistryGeorgia Institute of TechnologyAtlantaUSA
  3. 3.Department of Chemistry, College of Liberal ArtsMercer UniversityMaconUSA
  4. 4.Department of Medicinal Chemistry, School of PharmacyThe University of MississippiUniversityUSA