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

ABSTRACT: 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, 7b, 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 (+)-19m (later named bexicaserin), which displayed excellent oral bioavailability, good central nervous system partitioning, and decreased renal clearance in vivo. (+)-

SUBMITTER: Ren A 

PROVIDER: S-EPMC12169610 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature