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

Pettersson, Hanna ; Bülow, Anne ; Ek, Fredrik LU ; Jensen, Jacob LU ; Ottesen, Lars K. ; Fejzic, Alma ; Ma, Jian Nong ; Tredici, Andria L.Del ; Currier, Erika A. and Gardell, Luis R. , et al. (2009) In Journal of Medicinal Chemistry 52(7). p.1975-1982
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... (More)

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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publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Medicinal Chemistry
volume
52
issue
7
pages
8 pages
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:64549118196
  • pmid:19338356
ISSN
0022-2623
DOI
10.1021/jm801534c
language
English
LU publication?
no
id
1454f59e-ec3d-41d0-950c-d516d6812890
date added to LUP
2019-10-02 10:06:30
date last changed
2020-02-12 10:15:37
@article{1454f59e-ec3d-41d0-950c-d516d6812890,
  abstract     = {<p>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).</p>},
  author       = {Pettersson, Hanna and Bülow, Anne and Ek, Fredrik and Jensen, Jacob and Ottesen, Lars K. and Fejzic, Alma and Ma, Jian Nong and Tredici, Andria L.Del and Currier, Erika A. and Gardell, Luis R. and Tabatabaei, Ali and Craig, Darren and McFarland, Krista and Ott, Thomas R. and Piu, Fabrice and Burstein, Ethan S. and Olsson, Roger},
  issn         = {0022-2623},
  language     = {eng},
  month        = {04},
  number       = {7},
  pages        = {1975--1982},
  publisher    = {The American Chemical Society (ACS)},
  series       = {Journal of Medicinal Chemistry},
  title        = {Synthesis and evaluation of dibenzothiazepines : A novel class of selective cannabinoid-1 receptor inverse agonists},
  url          = {http://dx.doi.org/10.1021/jm801534c},
  doi          = {10.1021/jm801534c},
  volume       = {52},
  year         = {2009},
}