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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.
Smith BM,
Smith JM,
Tsai JH,
Schultz JA,
Gilson CA,
Estrada SA,
Chen RR,
Park DM,
Prieto EB,
Gallardo CS,
Sengupta D,
Dosa PI,
Covel JA,
Ren A,
Webb RR,
Beeley NR,
Martin M,
Morgan M,
Espitia S,
Saldana HR,
Bjenning C,
Whelan KT,
Grottick AJ,
Menzaghi F,
Thomsen WJ.
Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, California 92121, USA. bsmith@arenapharm.com
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.
PMID: 18095642 [PubMed - indexed for MEDLINE]
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