title: 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.
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.
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Thuy-Anh
authors.initials: TA
authors.lastname: Tran
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Bryan
authors.initials: B
authors.lastname: Kramer
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Shin
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Pureza
authors.initials: P
authors.lastname: Vallar
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: P Douglas
authors.initials: PD
authors.lastname: Boatman
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Zou
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Carleton R
authors.initials: CR
authors.lastname: Sage
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Tawfik
authors.initials: T
authors.lastname: Gharbaoui
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Biman
authors.initials: B
authors.lastname: Pal
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Sagar R
authors.initials: SR
authors.lastname: Shakya
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Antonio
authors.initials: A
authors.lastname: Garrido Montalban
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: John W
authors.initials: JW
authors.lastname: Adams
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Juan
authors.initials: J
authors.lastname: Ramirez
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Behan
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Shifrina
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Anthony
authors.initials: A
authors.lastname: Blackburn
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Tina
authors.initials: T
authors.lastname: Leakakos
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Abu
authors.initials: A
authors.lastname: Sadeque
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Weichao
authors.initials: W
authors.lastname: Chen
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Unett
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Ibragim
authors.initials: I
authors.lastname: Gaidarov
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Chen
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Steve
authors.initials: S
authors.lastname: Chang
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Hsin-Hui
authors.initials: HH
authors.lastname: Shu
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Shiu-Feng
authors.initials: SF
authors.lastname: Tung
authors.affiliation: Arena Pharmaceuticals , 6154 Nancy Ridge Drive, San Diego, California 92121, United States.
authors.forename: Graeme
authors.identifier: 0000-0002-9666-1588
authors.initials: G
authors.lastname: Semple
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002219:Carbamates / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055808:Drug Discovery; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D002219:Carbamates; D011982:Receptors, Prostaglandin; C000621069:ralinepag