Discovery of a lead series of potent benzodiazepine 5-HT2C receptor agonists with high selectivity in functional and binding assays. Issue 5 (1st March 2020)

• Record Type: Journal Article
• Authors: Ren, Albert; Zhu, Xiuwen; Feichtinger, Konrad; Lehman, Juerg; Kasem, Michelle; Schrader, Thomas O.; Wong, Amy; Dang, Huong; Le, Minh; Frazer, John; Unett, David J.; Grottick, Andrew J.; Whelan, Kevin T.; Morgan, Michael E.; Sage, Carleton R.; Semple, Graeme
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 5(2020)
• Publication Date: 2020-03-01
• Subjects: 5-HT2C receptor -- GPCR -- Agonist -- Lead identification; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.126929
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2C R agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6, 5, 7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.