Synthesis and evaluation of dibenzothiazepines: a novel class of selective cannabinoid-1 receptor inverse agonists.

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Pettersson H, Bulow A, Ek F, Jensen J, Ottesen LK, Fejzic A, Ma JN, Del Tredici AL, Currier EA, Gardell LR, Tabatabaei A, Craig D, McFarland K, Ott TR, Piu F, Burstein ES, Olsson R

Synthesis and evaluation of dibenzothiazepines: a novel class of selective cannabinoid-1 receptor inverse agonists.

J Med Chem. 2009 Apr 9;52(7):1975-82. doi: 10.1021/jm801534c.

PubMed ID

19338356 [ View in PubMed

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Abstract

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).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Rimonabant	Cannabinoid receptor 1	Ki (nM)	2	7.2	22	Details