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).
MeSH terms
-
Animals
-
Anti-Obesity Agents / chemical synthesis
-
Anti-Obesity Agents / chemistry
-
Anti-Obesity Agents / pharmacology
-
Appetite Depressants / chemical synthesis
-
Appetite Depressants / chemistry
-
Appetite Depressants / pharmacology
-
Cell Line
-
Combinatorial Chemistry Techniques
-
Dibenzothiazepines / chemical synthesis*
-
Dibenzothiazepines / chemistry
-
Dibenzothiazepines / pharmacology
-
Drug Inverse Agonism
-
Eating / drug effects
-
Humans
-
Hypothermia / chemically induced
-
In Vitro Techniques
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Radioligand Assay
-
Rats
-
Rats, Sprague-Dawley
-
Receptor, Cannabinoid, CB1 / agonists
-
Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
-
Solubility
-
Structure-Activity Relationship
-
Thiazepines / chemical synthesis*
-
Thiazepines / chemistry
-
Thiazepines / pharmacology
Substances
-
11-(3-chloro-4-fluorophenyl)dibenzo(b,f)(1,4)thiazepine-8-carboxylic acid butylamide
-
Anti-Obesity Agents
-
Appetite Depressants
-
Dibenzothiazepines
-
Receptor, Cannabinoid, CB1
-
Thiazepines