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

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Abstract 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 (AUCo-t = 26.7 h μg/mL), a prolonged half-life (t1/2 = 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.

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