Soluble guanylate cyclase (sGC) is a heme-containing enzyme and receptor of nitric oxide (NO). Binding of NO to the heme moiety activates sGC and catalyzes the conversion of guanosine-5’-tri-phosphate (GTP) to cyclic guanosine-3’, 5’-monophophate (cGMP). Stimulators of sGC are a class of compounds that agonize sGC independently of NO concentration and synergistically with NO. A clinical approval from this class of molecules has resulted in developments of other sGC stimulators. Beyond the well-established cardiopulmonary effects of sGC stimulators, they have potential as anti-fibrotic and anti-inflammatory agents.<br/><br/>Praliciguat is the first sGC stimulator from a new pyrazole-pyrimidine series to enter clinical development. The structure-activity-relationship and lead optimization efforts that led to the discovery of praliciguat began with profiling of various amines, and in particular, amino alcohols, at the 4-position of the pyrimidine ring. The desired potency, stability, PK-PD parameters and drug-like properties were achieved through multi-parameter optimization. Praliciguat is novel, orally bioavailable, high volume of distribution sGC stimulator possessing a PK profile consistent with once-daily dosing. It is currently in Phase II clinical trials for diabetic nephropathy and heart failure with preserved ejection fraction.

Discovery of Praliciguat (IW-1973): Novel, once daily, orally bioavailable, stimulator of soluble guanylate cyclase with extensive tissue distribution

2019 Fall National Meeting

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