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

Brian M. Smith; Jeffrey M. Smith; James H. Tsai; Jeffrey A. Schultz; Charles A. Gilson; Scott A. Estrada; Rita R. Chen; Douglas M. Park; Emily B. Prieto; Charlemagne S. Gallardo; Dipanjan Sengupta; Peter I. Dosa; Jon A. Covel; Albert Ren; Robert R. Webb; Nigel R.A. Beeley; Michael Martin; Michael Morgan; Stephen Espitia; Hazel R. Saldana; Christina Bjenning; Kevin T. Whelan; Andrew J. Grottick; Frederique Menzaghi; William J. Thomsen

doi:10.1021/jm0709034

Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5- tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT_2C receptor agonist for the treatment of obesity

Brian M. Smith, Jeffrey M. Smith, James H. Tsai, Jeffrey A. Schultz, Charles A. Gilson, Scott A. Estrada, Rita R. Chen, Douglas M. Park, Emily B. Prieto, Charlemagne S. Gallardo, Dipanjan Sengupta, Peter I. Dosa, Jon A. Covel, Albert Ren, Robert R. Webb, Nigel R.A. Beeley, Michael Martin, Michael Morgan, Stephen Espitia, Hazel R. SaldanaChristina Bjenning, Kevin T. Whelan, Andrew J. Grottick, Frederique Menzaghi, William J. Thomsen

Research output: Contribution to journal › Article › peer-review

193 Scopus citations

Abstract

The synthesis and SAR of a novel 3-benzazepine series of 5-HT_2C 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 [³H]phosphoinositol turnover: 5-HT _2C = 8.1; 5-HT_2A = 6.8; 5-HT_2B = 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 (t_1/2 = 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.

Original language	English (US)
Pages (from-to)	305-313
Number of pages	9
Journal	Journal of medicinal chemistry
Volume	51
Issue number	2
DOIs	https://doi.org/10.1021/jm0709034
State	Published - Jan 24 2008
Externally published	Yes

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10.1021/jm0709034

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Smith, B. M., Smith, J. M., Tsai, J. H., Schultz, J. A., Gilson, C. A., Estrada, S. A., Chen, R. R., Park, D. M., Prieto, E. B., Gallardo, C. S., Sengupta, D., Dosa, P. I., Covel, J. A., Ren, A., Webb, R. R., Beeley, N. R. A., Martin, M., Morgan, M., Espitia, S., ... Thomsen, W. J. (2008). Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5- tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT_2C receptor agonist for the treatment of obesity. Journal of medicinal chemistry, 51(2), 305-313. https://doi.org/10.1021/jm0709034

Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5- tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT_2C receptor agonist for the treatment of obesity. / Smith, Brian M.; Smith, Jeffrey M.; Tsai, James H. et al.
In: Journal of medicinal chemistry, Vol. 51, No. 2, 24.01.2008, p. 305-313.

Research output: Contribution to journal › Article › peer-review

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, NRA, Martin, M, Morgan, M, Espitia, S, Saldana, HR, Bjenning, C, Whelan, KT, Grottick, AJ, Menzaghi, F & Thomsen, WJ 2008, 'Discovery and structure-activity relationship of (1R)-8-chloro-2,3,4,5- tetrahydro-1-methyl-1H-3-benzazepine (Lorcaserin), a selective serotonin 5-HT_2C receptor agonist for the treatment of obesity', Journal of medicinal chemistry, vol. 51, no. 2, pp. 305-313. https://doi.org/10.1021/jm0709034

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title = "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",

abstract = "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 [3H]phosphoinositol turnover: 5-HT 2C = 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.",

author = "Smith, {Brian M.} and Smith, {Jeffrey M.} and Tsai, {James H.} and Schultz, {Jeffrey A.} and Gilson, {Charles A.} and Estrada, {Scott A.} and Chen, {Rita R.} and Park, {Douglas M.} and Prieto, {Emily B.} and Gallardo, {Charlemagne S.} and Dipanjan Sengupta and Dosa, {Peter I.} and Covel, {Jon A.} and Albert Ren and Webb, {Robert R.} and Beeley, {Nigel R.A.} and Michael Martin and Michael Morgan and Stephen Espitia and Saldana, {Hazel R.} and Christina Bjenning and Whelan, {Kevin T.} and Grottick, {Andrew J.} and Frederique Menzaghi and Thomsen, {William J.}",

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AU - Smith, Brian M.

AU - Smith, Jeffrey M.

AU - Tsai, James H.

AU - Schultz, Jeffrey A.

AU - Gilson, Charles A.

AU - Estrada, Scott A.

AU - Chen, Rita R.

AU - Park, Douglas M.

AU - Prieto, Emily B.

AU - Gallardo, Charlemagne S.

AU - Sengupta, Dipanjan

AU - Dosa, Peter I.

AU - Covel, Jon A.

AU - Ren, Albert

AU - Webb, Robert R.

AU - Beeley, Nigel R.A.

AU - Martin, Michael

AU - Morgan, Michael

AU - Espitia, Stephen

AU - Saldana, Hazel R.

AU - Bjenning, Christina

AU - Whelan, Kevin T.

AU - Grottick, Andrew J.

AU - Menzaghi, Frederique

AU - Thomsen, William J.

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N2 - 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 [3H]phosphoinositol turnover: 5-HT 2C = 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.

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