What question did this study set out to answer?

To synthesize and evaluate a novel series of 3-benzazepine 5-HT2C receptor agonists to discover a potent, selective drug candidate for obesity treatment.

December 21, 2007Journal of Medicinal ChemistryOpen Access

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

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To synthesize and evaluate a novel series of 3-benzazepine 5-HT2C receptor agonists to discover a potent, selective drug candidate for obesity treatment.
Synthesized a 3-benzazepine series and profiled in vitro potency and subtype selectivity across 5-HT2C, 5-HT2A, and 5-HT2B receptors using [3H]phosphoinositol turnover functional assays.
Evaluated oral pharmacokinetics, acute food intake after oral dosing, and chronic weight gain over a 28-day period in Sprague-Dawley rats.
Identified lorcaserin (compound 7d, APD356) as a potent, selective 5-HT2C agonist (pEC50 = 8.1) over 5-HT2A (pEC50 = 6.8) and 5-HT2B (pEC50 = 6.1).
Lorcaserin demonstrated favorable single-dose rat pharmacokinetics (half-life = 3.7 h; oral bioavailability = 86%) and reduced acute food intake with a 6-hour ED50 of 18 mg/kg.
Twice-daily oral dosing of lorcaserin at 36 mg/kg produced an 8.5% reduction in weight gain over 28 days in growing Sprague-Dawley rats.

Implication

Preclinical study demonstrates selective 5-HT2C receptor activation and weight gain reduction in rats, indicating therapeutic promise for 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 [(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.

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Cite This Study

Smith et al. (2007) studied this question.

synapsesocial.com/papers/6a967cd0a43071aed1f6a47b https://doi.org/10.1021/jm0709034

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Implication

Preclinical study demonstrates selective 5-HT2C receptor activation and weight gain reduction in rats, indicating therapeutic promise for obesity.

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

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Implication

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Discussion

Cite This Study

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

Key Points

Implication

Abstract

Discussion

Cite This Study

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