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J Med Chem. 2012 Nov 26;55(22):10022-32. doi: 10.1021/jm301181r. Epub 2012 Nov 9.

Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists.

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Discovery Sciences, Research Triangle Institute, 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 27709, USA.


Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS.

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