Discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol- 6(2H)-one, a selective, orally active agonist of the 5-HT(2C) receptor.
Robust pharmaceutical treatment of obesity has been limited by the undesirable side-effect profile of currently marketed therapies. This paper describes the synthesis and optimization of a new class of pyrazinoisoindolone-containing, selective 5-HT2C agonists as antiobesity agents. Key to optimization of the pyrazinoisoindolone core was the identification of the appropriate substitution pattern and functional groups which led to the discovery of (R)-9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino[2,1-a]isoindol-6(2H)-one (58), a 5-HT2C agonist with >300-fold functional selectivity over 5-HT2B and >70-fold functional selectivity over 5-HT2A. Oral dosing of 58 reduced food intake in an acute rat feeding model, which could be completely reversed by a selective 5-HT2C antagonist and caused a reduction in body weight gain in a 4-day rat model.
Wacker
Dean A
DA
Department of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. dean.wacker@bms.com
Varnes
Jeffrey G
JG
Malmstrom
Sarah E
SE
Cao
Xueying
X
Hung
Chen-Pin
CP
Ung
Thao
T
Wu
Ginger
G
Zhang
Ge
G
Zuvich
Eva
E
Thomas
Michael A
MA
Keim
William J
WJ
Cullen
Mary Jane
MJ
Rohrbach
Kenneth W
KW
Qu
Qinling
Q
Narayanan
Rangaraj
R
Rossi
Karen
K
Janovitz
Evan
E
Lehman-McKeeman
Lois
L
Malley
Mary F
MF
Devenny
James
J
Pelleymounter
Mary Ann
MA
Miller
Keith J
KJ
Robl
Jeffrey A
JA
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D003216:Conditioning, Operant; D005247:Feeding Behavior / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054833:Isoindoles; D008297:Male; D051379:Mice; D009336:Necrosis; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000473:pathology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058826:Serotonin 5-HT2 Receptor Agonists; D013237:Stereoisomerism; D015430:Weight Gain / Q000187:drug effects
C519109:9-ethyl-1,3,4,10b-tetrahydro-7-trifluoromethylpyrazino(2,1-a)isoindol-6(2H)-one; D019440:Anti-Obesity Agents; D007211:Indoles; D054833:Isoindoles; D011719:Pyrazines; D058826:Serotonin 5-HT2 Receptor Agonists