Diazepine Agonists of the 5-HT_2C Receptor with Unprecedented Selectivity: Discovery of Bexicaserin (LP352)

The clinical development of novel 5-HT_2C receptor (5-HT_2CR) therapies has been limited due to concerns over lack of selectivity and potential for off-target effects. Here, we report that the introduction of a secondary amide substituent into a 6,5,7-tricyclic benzodiazepine scaffold provided compounds with unprecedented selectivity for the 5-HT_2CR in both functional and binding assays. An early lead compound, <b>7b</b>, had an in vivo half-life that was shorter than desired, which was improved by a targeted reduction in renal clearance. This provided the clinical candidate compound <b>(+)-19m</b> (later named bexicaserin), which displayed excellent oral bioavailability, good central nervous system partitioning, and decreased renal clearance in vivo. <b>(+)-19m</b> was also a potent inhibitor of acute refeeding in the fasted rat, suggesting on-target effects. <b>(+)-19m</b> demonstrated excellent selectivity for 5-HT_2CR over 5-HT_2AR and 5-HT_2BR and maximal activity exceeding that induced by the endogenous ligand 5-HT. <b>(+)-19m</b> has since progressed into clinical development.