New bicyclic cannabinoid receptor-1 (CB1-R) antagonists

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• The human cannabinoid receptor type 1 (hCB(1)-R) is a key target for various physiological processes.
• SR141716 is a known modulator of hCB(1)-R, serving as a basis for developing new chemical entities.
• Conformationally constrained bicyclic derivatives offer unique pharmacological profiles.

Purpose of the Study:

• To synthesize and evaluate novel bicyclic derivatives as antagonists and inverse agonists of hCB(1)-R.
• To optimize structure-activity relationships (SAR) for enhanced hCB(1)-R antagonism.
• To identify compounds with potential oral bioavailability and efficacy in relevant models.

Main Methods:

• Synthesis of a series of conformationally constrained bicyclic compounds based on the SR141716 scaffold.
• In vitro evaluation of synthesized compounds for binding affinity and functional activity at hCB(1)-R.
• In vivo assessment of selected compounds in rodent feeding models to determine oral activity.

Main Results:

• The 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a served as a lead structure for SAR optimization.
• Two compounds, 2h and 4a, emerged with significant oral activity in rodent feeding models.
• Modification of the bicyclic group in compound 2h led to a decrease in binding affinity, highlighting the importance of this structural feature.

Conclusions:

• Novel bicyclic derivatives targeting hCB(1)-R were successfully synthesized and characterized.
• Compounds 2h and 4a represent promising leads with oral efficacy, warranting further investigation.
• The specific bicyclic moiety is crucial for maintaining high binding affinity to hCB(1)-R.