Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core

Pakornwit Sarnpitak, Prashant Mujumdar, Christophe Morisseau, Sung Hee Hwang, Bruce Hammock, Vladimir Iurchenko, Sergey Zozulya, Antonis Gavalas, Athina Geronikaki, Yan Ivanenkov, Mikhail Krasavin

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27 Citations (Scopus)


A novel series of compounds containing a polar, non-flat 2-imidazoline core was designed based on the SAR information available for aromatic azole cyclooxygenase-2 inhibitors. While the majority of the compounds prepared using an earlier developed imidazoline N-arylation methodology turned out to be inferior to the known COX-2 inhibitors, one lead compound displayed potency (300 nM) comparable to clinically used Celecoxib and was shown to be more selective. The series represents the first example of selective COX-2 inhibitors built around a distinctly polar core, contradicting an earlier accepted view that a lipophilic scaffold is required for high inhibitor potency. The lead compound demonstrated very good oral bioavailability in mice, slow metabolic degradation, modest distribution into the brain and a remarkable anti-inflammatory efficacy in carrageenan-induced mouse paw edema model. A foundation has therefore been laid for a chemically novel series of COX-2 inhibitors that has a potential for diverse therapeutic applications in inflammatory disease area.

Original languageEnglish
Pages (from-to)160-172
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 12 Sep 2014
Externally publishedYes


  • Amidines
  • Anti-inflammatory
  • Blood-brain barrier
  • Coxibs
  • High-sp3
  • Mouse paw edema
  • Non-aromatic

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