title: 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.
abstract: 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.
authors.affiliation: F. Hoffmann-La Roche Ltd, Discovery Research, 4070 Basel, Switzerland. hans.richter@roche.com
authors.forename: Hans G F
authors.initials: HG
authors.lastname: Richter
authors.forename: D R
authors.initials: DR
authors.lastname: Adams
authors.forename: A
authors.initials: A
authors.lastname: Benardeau
authors.forename: M J
authors.initials: MJ
authors.lastname: Bickerdike
authors.forename: J M
authors.initials: JM
authors.lastname: Bentley
authors.forename: T J
authors.initials: TJ
authors.lastname: Blench
authors.forename: I A
authors.initials: IA
authors.lastname: Cliffe
authors.forename: C
authors.initials: C
authors.lastname: Dourish
authors.forename: P
authors.initials: P
authors.lastname: Hebeisen
authors.forename: G A
authors.initials: GA
authors.lastname: Kennett
authors.forename: A R
authors.initials: AR
authors.lastname: Knight
authors.forename: C S
authors.initials: CS
authors.lastname: Malcolm
authors.forename: P
authors.initials: P
authors.lastname: Mattei
authors.forename: A
authors.initials: A
authors.lastname: Misra
authors.forename: J
authors.initials: J
authors.lastname: Mizrahi
authors.forename: N J T
authors.initials: NJ
authors.lastname: Monck
authors.forename: J-M
authors.initials: JM
authors.lastname: Plancher
authors.forename: S
authors.initials: S
authors.lastname: Roever
authors.forename: J R A
authors.initials: JR
authors.lastname: Roffey
authors.forename: S
authors.initials: S
authors.lastname: Taylor
authors.forename: S P
authors.initials: SP
authors.lastname: Vickers
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D006900:Hydroxylation; D015394:Molecular Structure; D010743:Phospholipids / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry*; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists; D013329:Structure-Activity Relationship
chemical_list: D010743:Phospholipids; D011719:Pyrazines; D011758:Pyrroles; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists