Synthesis and evaluation of dibenzothiazepines : A novel class of selective cannabinoid-1 receptor inverse agonists
(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).
(Less)
- author
- publishing date
- 2009-04-09
- 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
-
- pmid:19338356
- scopus:64549118196
- 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
- 2024-06-12 02:21:34
@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}}, }