Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT2C receptor agonist for the treatment of obesity.
The synthesis and SAR of a novel 3-benzazepine series of 5-HT2C agonists is described. Compound 7d (lorcaserin, APD356) was identified as one of the more potent and selective compounds in vitro (pEC50 values in functional assays measuring [(3)H]phosphoinositol turnover: 5-HT2C = 8.1; 5-HT2A = 6.8; 5-HT2B = 6.1) and was potent in an acute in vivo rat food intake model upon oral administration (ED50 at 6 h = 18 mg/kg). Lorcaserin was further characterized in a single-dose pharmacokinetic study in rat (t1/2 = 3.7 h; F = 86%) and a 28-day model of weight gain in growing Sprague-Dawley rat (8.5% decrease in weight gain observed at 36 mg/kg b.i.d.). Lorcaserin was selected for further evaluation in clinical trials for the treatment of obesity.
Smith
Brian M
BM
Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, California 92121, USA. bsmith@arenapharm.com
Smith
Jeffrey M
JM
Tsai
James H
JH
Schultz
Jeffrey A
JA
Gilson
Charles A
CA
Estrada
Scott A
SA
Chen
Rita R
RR
Park
Douglas M
DM
Prieto
Emily B
EB
Gallardo
Charlemagne S
CS
Sengupta
Dipanjan
D
Dosa
Peter I
PI
Covel
Jon A
JA
Ren
Albert
A
Webb
Robert R
RR
Beeley
Nigel R A
NR
Martin
Michael
M
Morgan
Michael
M
Espitia
Stephen
S
Saldana
Hazel R
HR
Bjenning
Christina
C
Whelan
Kevin T
KT
Grottick
Andrew J
AJ
Menzaghi
Frederique
F
Thomsen
William J
WJ
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004435:Eating / Q000187:drug effects; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D009765:Obesity / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058826:Serotonin 5-HT2 Receptor Agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015430:Weight Gain / Q000187:drug effects
D019440:Anti-Obesity Agents; D001552:Benzazepines; D058826:Serotonin 5-HT2 Receptor Agonists; C506658:lorcaserin; D015544:Inositol 1,4,5-Trisphosphate