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

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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 (US)
Pages (from-to)160-172
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume84
DOIs
StatePublished - Sep 12 2014

Fingerprint

Cyclooxygenase 2 Inhibitors
Lead compounds
Celecoxib
Imidazolines
Azoles
Carrageenan
Scaffolds
Biological Availability
Edema
Brain
Anti-Inflammatory Agents
Degradation
2-imidazoline
Lead
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Sarnpitak, P., Mujumdar, P., Morisseau, C., Hwang, S. H., Hammock, B., Iurchenko, V., ... Krasavin, M. (2014). Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core. European Journal of Medicinal Chemistry, 84, 160-172. https://doi.org/10.1016/j.ejmech.2014.07.023

Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core. / Sarnpitak, Pakornwit; Mujumdar, Prashant; Morisseau, Christophe; Hwang, Sung Hee; Hammock, Bruce; Iurchenko, Vladimir; Zozulya, Sergey; Gavalas, Antonis; Geronikaki, Athina; Ivanenkov, Yan; Krasavin, Mikhail.

In: European Journal of Medicinal Chemistry, Vol. 84, 12.09.2014, p. 160-172.

Research output: Contribution to journalArticle

Sarnpitak, P, Mujumdar, P, Morisseau, C, Hwang, SH, Hammock, B, Iurchenko, V, Zozulya, S, Gavalas, A, Geronikaki, A, Ivanenkov, Y & Krasavin, M 2014, 'Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core', European Journal of Medicinal Chemistry, vol. 84, pp. 160-172. https://doi.org/10.1016/j.ejmech.2014.07.023
Sarnpitak, Pakornwit ; Mujumdar, Prashant ; Morisseau, Christophe ; Hwang, Sung Hee ; Hammock, Bruce ; Iurchenko, Vladimir ; Zozulya, Sergey ; Gavalas, Antonis ; Geronikaki, Athina ; Ivanenkov, Yan ; Krasavin, Mikhail. / Potent, orally available, selective COX-2 inhibitors based on 2-imidazoline core. In: European Journal of Medicinal Chemistry. 2014 ; Vol. 84. pp. 160-172.
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