American Chemical Society
jm801534c_si_004.pdf (1.28 MB)

Synthesis and Evaluation of Dibenzothiazepines: A Novel Class of Selective Cannabinoid-1 Receptor Inverse Agonists

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journal contribution
posted on 2009-04-09, 00:00 authored by Hanna Pettersson, Anne Bülow, Fredrik Ek, Jacob Jensen, Lars K. Ottesen, Alma Fejzic, Jian-Nong Ma, Andria L. Del Tredici, Erika A. Currier, Luis R. Gardell, Ali Tabatabaei, Darren Craig, Krista McFarland, Thomas R. Ott, Fabrice Piu, Ethan S. Burstein, Roger Olsson
A novel class of CB1 inverse agonists was discovered. To efficiently establish structure−activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing recombinant human cannabinoid receptors (CB1 and CB2). In general, all of the compounds exhibited high binding selectivity at CB1 vs CB2 and the general SAR revealed a lead compound 11-(4-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12e) which showed excellent in vivo activity in pharmacodynamic models related to CB1 receptor activity. The low solubility that hampered the development of 12e was solved leading to a potential preclinical candidate 11-(3-chloro-4-fluorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12h).