Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists
ACS Medicinal Chemistry Letters2014Vol. 6(2), pp. 156–161
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Suvi T. M. Orr, Ramsay E. Beveridge, Samit K. Bhattacharya, Kimberly O. Cameron, Steven B. Coffey, Dilinie P. Fernando, David Hepworth, Margaret Jackson, Vishal Khot, Rachel E. Kosa, Kimberly Lapham, Paula M. Loria, Kim F. McClure, Jigna D. Patel, Colin R. Rose, James Sáenz, Ingrid A. Stock, Gregory Storer, Maria von Volkenburg, Derek Vrieze, Guoqiang Wang, Jun Xiao, Yingxin Zhang
Abstract
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.
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