Synthesis and biological evaluation of novel hexahydro-pyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT2C receptor agonists

Further lead optimization efforts on previously described 1,2,3,4,10,10a-hexahydro-1H-pyrazino[1,2-a]indoles led to the new class of 5,5a,6,7,8,9-hexahydro-pyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazines culminating in the discovery of (5aR,9R)-2-[(cyclopropylmethoxy)methyl]-5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3′, 2′:4,5]pyrrolo[1,2-a]pyrazine 18 as a potent, full 5-HT2C receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.

Graphical abstractA novel series of chiral 5,5a,6,7,8,9-hexahydro-9-methyl-pyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT2C receptor agonists has been discovered. Several analogues had low potential to induce phospholipidosis in vitro and showed low affinity for the hERG potassium channel.Figure optionsDownload full-size imageDownload as PowerPoint slide