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.
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.
Richter
Hans G F
HG
F. Hoffmann-La Roche Ltd, Discovery Research, 4070 Basel, Switzerland. hans.richter@roche.com
Adams
D R
DR
Benardeau
A
A
Bickerdike
M J
MJ
Bentley
J M
JM
Blench
T J
TJ
Cliffe
I A
IA
Dourish
C
C
Hebeisen
P
P
Kennett
G A
GA
Knight
A R
AR
Malcolm
C S
CS
Mattei
P
P
Misra
A
A
Mizrahi
J
J
Monck
N J T
NJ
Plancher
J-M
JM
Roever
S
S
Roffey
J R A
JR
Taylor
S
S
Vickers
S P
SP
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
D010743:Phospholipids; D011719:Pyrazines; D011758:Pyrroles; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists