Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator.
Rennie GR, Barden TC, Bernier SG, Carvalho A, Deming R, Germano P, Hudson C, Im GJ, Iyengar RR, Jia L, Jung J, Kim E, Lee TW, Mermerian A, Moore J, Nakai T, Perl NR, Tobin J, Zimmer DP, Renhowe PA.
Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.