Synthesis and biological evaluation of novel hexahydro-pyrido[3',2':4,5]pyrrolo[1,2-a]pyrazines as potent and selective 5-HT(2C) receptor agonists.
Richter HGF., Adams DR., Benardeau A., Bickerdike MJ., Bentley JM., Blench TJ., Cliffe IA., Dourish C., Hebeisen P., Kennett GA., Knight AR., Malcolm CS., Mattei P., Misra A., Mizrahi J., Monck NJT., Plancher J-M., Roever S., Roffey JRA., Taylor S., Vickers SP.
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-HT(2C) receptor agonist with an outstanding selectivity profile and excellent hERG and phospholipidosis properties.