Design, Synthesis, and Evaluation of Diphenylpyrazinyl Amino Cycloalkoxy Acetic Acids as IP Receptor Agonists.

To address the pharmacokinetic limitations and moderate potency of current prostanoid IP receptor agonists for treating pulmonary arterial hypertension, we developed a series of conformationally constrained diphenylpyrazinyl amino cycloalkoxy acetic acids. By replacing the flexible side chain of MRE-269 with a rigid cyclic framework, we locked the bioactive conformation, identifying 7a-5 and its deuterated analog 7a-19. Compound 7a-19 exhibited potent antiaggregatory activity (IC50 = 0.97 μM), a 7-fold enhancement over MRE-269 (IC50 = 7.4 μM). Crucially, leveraging the deuterium kinetic isotope effect in rats, 7a-19 demonstrated an 11-fold increase in systemic exposure (AUC o‑t = 26.7 h μg/mL), a prolonged half-life (t 1/2 = 12.0 h), and excellent oral bioavailability (F = 47.3%). Combined with a clean safety profile in the Mini-Ames assay and a lack of hERG inhibition (IC50 = 143.1 μM), 7a-19 stands out as a robust, long-acting lead candidate for PAH therapy.