Decreased signaling at the 5-HT2C receptor appears to play a major role in schizophrenia, bipolar depression, psychosis in Alzheimer’s Disease, drug addiction and also in obesity. Stimulation of the 5-HT2C receptor has been shown to be efficacious in preclinical animal models of psychosis, substance abuse disorders and food intake. Selectivity versus the closely related 5-HT2A and the 5-HT2B receptor is crucial, since 5-HT2A agonism has hallucinogenic properties and stimulation of the 5-HT2B receptor increases the risk of heart valve damage. Starting from a published lead compound with good potency and selectivity but with a poor ADME profile including low oral bioavailability, systematic investigation of the site of metabolism and subsequent dedicated structural modification of the metabolic hotspot led to compounds with significantly improved oral bioavailability across species, while maintaining a favorable activity and selectivity profile. Moreover, improving brain penetration by additional modifications led to advanced lead candidates with an exciting preclinical profile regarding dose-dependent in vivo efficacy in a number of animal models, cardiovascular safety and acute and repeat-dose toxicology, yielding promising candidates with the potential for an improved first-in-class neurotherapeutic.

Discovery of novel potent and selective agonists of the serotonin (5-HT) 5-HT2C receptor as neurotherapeutics

253rd National Meeting (2017)

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