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

作者：Sarnpitak Pakornwit; Mujumdar Prashant; Morisseau Christophe; Hwang Sung Hee; Hammock Bruce; Iurchenko Vladimir; Zozulya Sergey; Gavalas Antonis; Geronikaki Athina; Ivanenkov Yan; Krasavin Mikhail^*

来源：European Journal of Medicinal Chemistry, 2014, 84: 160-172.

DOI：10.1016/j.ejmech.2014.07.023

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

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.

• 出版日期2014-9-12