2,3-Dihydro-1-benzofuran derivatives as a series of potent selective cannabinoid receptor 2 agonists: design, synthesis, and binding mode prediction through ligand-steered modeling.

Philippe Diaz, Sharangdhar S Phatak, Jijun Xu, Frank R Fronczek, Fanny Astruc-Diaz, Charles M Thompson, Claudio N Cavasotto, Mohamed Naguib

Index: ChemMedChem 4(10) , 1615-29, (2009)

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Abstract

We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB(2)) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB(2) agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 (compound 19) and MDA39 (compound 30) were the most potent at CB(2). MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.