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

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>5c</b> (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>5c</b> 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>5c</b> was selected for further development for the treatment of PAH

(7‑Benzyloxy-2,3-dihydro-<i>1H</i>-pyrrolo[1,2‑<i>a</i>]indol-1-yl)acetic Acids as S1P₁ Functional Antagonists

S1P₁ is a validated target for treatment of autoimmune disease, and functional antagonists with superior safety and pharmacokinetic properties are being sought as second generation therapeutics. We describe the discovery and optimization of (7-benzyloxy-2,3-dihydro-<i>1H</i>-pyrrolo­[1,2-<i>a</i>]­indol-1-yl)­acetic acids as potent, centrally available, direct acting S1P₁ functional antagonists, with favorable pharmacokinetic and safety properties