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

Authors
  • Pettersson, Hanna
  • Bülow, Anne
  • Ek, Fredrik
  • Jensen, Jacob
  • Ottesen, Lars K
  • Fejzic, Alma
  • Ma, Jian-Nong
  • Del Tredici, Andria L
  • Currier, Erika A
  • Gardell, Luis R
  • Tabatabaei, Ali
  • Craig, Darren
  • McFarland, Krista
  • Ott, Thomas R
  • Piu, Fabrice
  • Burstein, Ethan S
  • Olsson, Roger
Type
Published Article
Journal
Journal of Medicinal Chemistry
Publisher
American Chemical Society
Publication Date
Apr 09, 2009
Volume
52
Issue
7
Pages
1975–1982
Identifiers
DOI: 10.1021/jm801534c
PMID: 19338356
Source
Medline
License
Unknown

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).

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