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Methylsulfonylpyrazolyl oxadiazoles and thiadiazoles as potent, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity
- Source :
- Future medicinal chemistry. 1(5)
- Publication Year :
- 2011
-
Abstract
- Background: Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Discussion: In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity. Results: The structure–activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC50 values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.
- Subjects :
- Cannabinoid 1 receptor
Cannabinoid receptor
Administration, Oral
Biological Availability
Pharmacology
Pyrazole
chemistry.chemical_compound
Mice
Structure-Activity Relationship
Thiadiazoles
Rimonabant
Receptor, Cannabinoid, CB1
Drug Discovery
medicine
Animals
Humans
Computer Simulation
Obesity
Oxadiazoles
Binding Sites
Chemistry
Antagonist
Bioavailability
Rats
Biochemistry
Molecular Medicine
Pyrazoles
Anti-Obesity Agents
Antagonism
medicine.drug
Subjects
Details
- ISSN :
- 17568927
- Volume :
- 1
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Future medicinal chemistry
- Accession number :
- edsair.doi.dedup.....9dc09fa305cb20dda0aa037d490db33b