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.

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate‐release oral formulation in healthy volunteers

“…The observed “double peaking” 17 seen after single dosing, particularly evident at higher dose levels, suggests that ralinepag may undergo some enterohepatic recirculation in humans and as previously reported in animals. 15 From the single-dose study, ralinepag was determined to have a long mean terminal elimination half-life (up to 26.4 h). From the multiple-dose study, the ralinepag QD and BID regimens provided steady-state peak-to-trough values ranging from 3.34–4.49 and 1.95–2.36, respectively, with the latter approaching the clinical ideal of ∼1.0–2.0 and which reflects a relatively flat PK profile that is unique and considered highly favorable in comparison to that achieved with other oral agents in this drug class such as treprostinil and selexipag.…”

“…In nonclinical testing, ralinepag demonstrated dose-dependent oral efficacy in a rat monocrotaline model of PAH, moderate to high oral bioavailability across evaluated animal species (mouse, rat, dog, and monkey), high plasma protein binding ($99%) in animals and humans, and relatively long mean terminal half-life values across animal species ranging from 5.5 to 39 h. 15 Enterohepatic recirculation of ralinepag was also observed in animals that may further contribute to its prolonged systemic exposure. 15 The aims of the present single ascending dose (SAD) and multiple ascending dose (MAD) studies were to evaluate the safety, tolerability, and PK of single and multiple ascending oral doses of a ralinepag immediate-release (IR) capsule formulation in healthy human volunteers. The findings from these two studies were used to support further clinical development of the compound, determine the optimal frequency of administration of the ralinepag IR capsule formulation in Phase 2 clinical testing, and help optimize the up-titration dosing schedule to potentially enhance tolerability.…”

Diverse Pharmacology of Prostacyclin Mimetics: Implications for Pulmonary Hypertension

“…TP, FP, EP 1 and EP 3 receptors are contractile receptors coupled to Gq and Gi that either elevate intracellular Ca 2+ and/or reduce cAMP, respectively. EP 2 , EP 4 , IP and DP 1 receptors are vasorelaxant receptors coupled to Gs that will activate adenylate cyclase and elevate intracellular cAMP selective IP receptor agonists were recently synthesised, with ralinepag (APD811) in clinical development as a next generation, once a day oral for the treatment of PAH [35]. Other novel approaches are being taken, including the development of ONO-1301, a non-prostanoid with a dual function of activating the IP receptor and inhibiting TXA 2 synthase [24].…”

“…All prostacyclin mimetics used clinically display high affinity binding to the human IP receptor. Potency varies, with those having a Ki of 2-4 nM (prostacyclin, iloprost and ralinepag) and those having a tenfold lower affinity with a Ki of 20-38 nM (MRE-269, treprostinil and beraprost), or lower still, with selexipag having a Ki of 250 nM [6,35]. Esuberaprost (beraprost-314d), a reformulated single isomer of beraprost, may be the most potent IP agonist developed so far for therapeutic use [36] and is now in a phase III clinical trial as an oral with inhaled treprostinil.…”

“…Mechanistic and functional differences between prostanoid and non-prostanoid IP agonists are now beginning to emerge that need to be carefully considered in a clinical context. Both ralinepag and MRE-269 behave as partial agonists in cAMP assays in CHO cells stably expressing the human IP receptor and in human PASMCs from PAH patients [35,37,38]. Partial agonism may in part explain why MRE-269 was about 65-fold less potent than iloprost at inhibiting contractions in human pulmonary arteries [19] and why selexipag has little overall effect on platelet aggregation in vivo [39].…”