MK-2947

Endothelial dysfunction and impaired NO-sGC - cGMP signaling in hypertension drive the need for next-generation soluble guanylate cyclase (sGC) stimulators with improved pharmacokinetics and once-daily dosing potential. Metabolism-guided optimization of MK-2947, which showed robust preclinical blood pressure lowering but exhibited compound-specific toxicity and a projected human half-life of ∼12 h, led to the identification of compound 20, a potent sGC stimulator (EC₅₀ = 44 nM) with improved pharmacokinetics and sustained blood pressure lowering in preclinical models (≥24 h). Preclinical PK/PD data support compound 20 as a structurally differentiated sGC stimulator with a profile consistent with once-daily dosing potential, reflecting an improved balance of pharmacokinetic and pharmacodynamic properties, pending further safety evaluation.