Discovery and Development of Next Generation sGC Stimulators with Diverse Multidimensional Pharmacology and Broad Therapeutic Potential

Nitric Oxide (2018)

E.S. Buys, D.P. Zimmer, J. Chickering, R. Graul, Y.T. Chien, A. Profy, J.R. Hadcock, J.L. Masferrer, G.T. Milne

This article provides an introduction to the central role of nitric oxide-sGC-cGMP signaling in health and disease and an overview of the sGC stimulators being developed by Cyclerion (Ironwood Pharmaceuticals at the time of publication), with an emphasis on olinciguat and praliciguat.

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Multi-dimensional pharmacology of sGC stimulators

Soluble guanylate cyclase (sGC), an enzyme that catalyzes the formation of cyclic guanosine-3′,5′-monophophate (cGMP) from guanosine triphosphate (GTP) in response to nitric oxide (NO), is a key mediator of neuronal, inflammatory, and smooth muscle cell function. Orally available sGC stimulators enhance NO-sGC-cGMP signaling and demonstrate metabolic, blood pressure lowering, as well as anti-inflammatory and anti-fibrotic effects.