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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.

In animals, increased lung volume and a concomitant failure of lungs to collapse normally upon autopsy can occur following intravenous injection of higher vapor pressure perfluorocarbons (PFCs) administered as emulsions. Responses vary considerably depending on the PFC, dose and animal model. The study objective was to examine animal species differences with respect to this apparent pulmonary gas trapping (PGT) phenomenon which has not been observed in human clinical trials. A dose-related increase in postmortem lung volume following treatment with either a concentrated perflubron emulsion or Fluosol was observed. It was most pronounced in pigs, rabbits and monkeys, and essentially nonexistent in mice and dogs. No clear effects on arterial blood gases were seen in most species, but PaO2 levels were reduced transiently in monkeys given the highest PFC doses. Reversibility of pulmonary effects occurred more rapidly with perflubron emulsions than with Fluosol. Vacuolated mononuclear cells, reflecting the presence of PFC particles in the lung, and alveolar distention varied between species, but no lesions or edema were observed. Species differences in collateral ventilation, airway morphology and pulmonary intravascular macrophages may influence their sensitivity and contribute to the interspecies differences in response to intravenously administered PFC emulsions.

Experimental observations are consistent with the proposed theory of perfluorocarbon-related gas osmosis through micro-bubbles that prevent complete lung collapse as observed upon opening the thoracic cavity of test animals.

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