American Chemical Society
jm6b00871_si_001.pdf (1.68 MB)

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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journal contribution
posted on 2017-01-10, 00:00 authored by 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
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 5c (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. 5c 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, 5c was selected for further development for the treatment of PAH.