2. Academic Validation
  3. 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

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

  • J Med Chem. 2017 Feb 9;60(3):913-927. doi: 10.1021/acs.jmedchem.6b00871.
Thuy-Anh Tran 1,  Bryan Kramer 1,  Young-Jun Shin 1,  Pureza Vallar 1,  P Douglas Boatman 1,  Ning Zou 1,  Carleton R Sage 1,  Tawfik Gharbaoui 1,  Ashwin Krishnan 1,  Biman Pal 1,  Sagar R Shakya 1,  Antonio Garrido Montalban 1,  John W Adams 1,  Juan Ramirez 1,  Dominic P Behan 1,  Anna Shifrina 1,  Anthony Blackburn 1,  Tina Leakakos 1,  Yunqing Shi 1,  Michael Morgan 1,  Abu Sadeque 1,  Weichao Chen 1,  David J Unett 1,  Ibragim Gaidarov 1,  Xiaohua Chen 1,  Steve Chang 1,  Hsin-Hui Shu 1,  Shiu-Feng Tung 1,  Graeme Semple 1
Affiliations

Affiliation

  • 1 Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
PMID: 28072531 DOI: 10.1021/acs.jmedchem.6b00871
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z