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
Version 2 2024-11-27, 18:05Version 2 2024-11-27, 18:05
Version 1 2017-01-19, 18:33Version 1 2017-01-19, 18:33
journal contribution
posted on 2024-11-27, 18:05authored byThuy-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.