Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

• Published in: ACS medicinal chemistry letters Vol. 6; no. 2; pp. 156 - 161
• Main Authors: Orr, Suvi T. M, Beveridge, Ramsay, Bhattacharya, Samit K, Cameron, Kimberly O, Coffey, Steven, Fernando, Dilinie, Hepworth, David, Jackson, Margaret V, Khot, Vishal, Kosa, Rachel, Lapham, Kimberly, Loria, Paula M, McClure, Kim F, Patel, Jigna, Rose, Colin, Saenz, James, Stock, Ingrid A, Storer, Gregory, von Volkenburg, Maria, Vrieze, Derek, Wang, Guoqiang, Xiao, Jun, Zhang, Yingxin
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-02-2015
• Subjects: Letter; growth hormone secretagogue receptor 1a; Heteroaryl acetic acid; ghrelin; carboxamide; type 2 diabetes; spiroazetidine-piperidine
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/ml500414n

Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series.