ABSTRACT
A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.
Subject(s)
Receptor, Serotonin, 5-HT2C/metabolism , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Dose-Response Relationship, Drug , Humans , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Molecular Structure , Rats , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/chemistry , Structure-Activity RelationshipABSTRACT
The syntheses, structure-activity relationships (SARs), and biological activities of tetrahydroquinoline-based tricyclic amines as 5-HT2C receptor agonists are reported. An early lead containing a highly unique 6,6,7-ring system was optimized for both in vitro potency and selectivity at the related 5-HT2B receptor. Orally bioactive, potent, and selective 6,6,6-tricyclic 5-HT2C agonists were identified.
