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

The clinical development of novel 5-HT receptor (5-HTR) 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-HTR in both functional and binding assays. An early lead compound, , 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 (later named bexicaserin), which displayed excellent oral bioavailability, good central nervous system partitioning, and decreased renal clearance in vivo. was also a potent inhibitor of acute refeeding in the fasted rat, suggesting on-target effects. demonstrated excellent selectivity for 5-HTR over 5-HTR and 5-HTR and maximal activity exceeding that induced by the endogenous ligand 5-HT. has since progressed into clinical development.