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.
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.
Diaz
Philippe
P
Core Laboratory for Neuromolecular Production, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, 32 Campus Drive, Missoula, MT 59812 (USA).
Phatak
Sharangdhar S
SS
Xu
Jijun
J
Fronczek
Frank R
FR
Astruc-Diaz
Fanny
F
Thompson
Charles M
CM
Cavasotto
Claudio N
CN
Naguib
Mohamed
M
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013329:Structure-Activity Relationship
D018712:Analgesics, Non-Narcotic; D001572:Benzofurans; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; C043168:coumaran