Constrained analogs of CB-1 antagonists: 1,5,6,7-Tetrahydro-4H-pyrrolo[3,2-c]pyridine-4-one derivatives

A series of pyrrolopyridinones was designed and synthesized as constrained analogs of the pyrazole CB-1 antagonist rimonabant. Certain examples exhibited very potent hCB-1 receptor binding affinity and functional antagonism with Ki and Kb values below 10 nM, and with high selectivity for CB-1 over CB-2 (>100-fold). A representative analog was established to cause significant appetite suppression and reduction in body weight gain in industry-standard rat models used to develop new therapeutics for obesity.

Graphical abstractPyrrolopyridinones were designed and established as potent constrained analogs of the pyrazole CB-1 receptor antagonist/inverse agonist rimonabant. A representative analog was also demonstrated to cause significant appetite suppression and reduction in body weight gain in rodent models.Figure optionsDownload full-size imageDownload as PowerPoint slide