Discovery of 2-(((1r,4r)-4-(((4-Chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetate (Ralinepag): An Orally Active Prostacyclin Receptor Agonist for the Treatment of Pulmonary Arterial Hypertension

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• 作者：Thuy-Anh Tran ; Bryan Kramer ; Young-Jun Shin ; Pureza Vallar ; P. Douglas Boatman ; Ning Zou ; Carleton R. Sage ; Tawfik Gharbaoui ; Ashwin Krishnan ; Biman Pal ; Sagar R. Shakya ; Antonio Garrido Montalban ; John W. Adams ; Juan Ramirez ; Dominic P. Behan ; Anna Shifrina ; Anthony Blackburn ; Tina Leakakos ; Yunqing Shi ; Michael Morgan ; Abu Sadeque ; Weichao Chen ; David J. Unett ; Ibragim Gaidarov ; Xiaohua Chen ; Steve Chang ; Hsin-Hui Shu ; Shiu-Feng Tung ; Graeme Semple
• 刊名：Journal of Medicinal Chemistry
• 出版年：2017
• 出版时间：February 9, 2017
• 年：2017
• 卷：60
• 期：3
• 页码：913-927
• 全文大小：453K
• ISSN：1520-4804

文摘

The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of <b>5cb> (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays. <b>5cb> had an excellent PK profile across species. Enterohepatic recirculation most probably contributes to a concentration–time profile after oral administration in the cynomolgus monkey that showed a very low peak-to-trough ratio. Following the identification of an acceptable solid form, <b>5cb> was selected for further development for the treatment of PAH.