Soluble Guanylate Cyclase (sGC), a heme containing enzyme, is the effector of endogenous nitric oxide (NO) and catalyzes the production of cGMP from GTP. The NO-sGC-cGMP signaling pathway plays a key role in the cardiovascular system regulating smooth muscle relaxation and vasodilation and has been implicated in remodeling events in the heart and vasculature. Small molecule stimulators of sGC have been identified that are able to directly target the native heme-containing reduced form of the enzyme, acting on the enzyme in the absence of, or in synergy with NO. The therapeutic potential of sGC stimulators is illustrated by the successful approval of ADEMPASä for the treatment of pulmonary hypertension. We have discovered a novel class of sGC stimulators that are potent, selective and have excellent <i>in vivo</i> efficacy in rodent models of hypertension. This talk will describe the synthesis, SAR optimization, and the pharmacodynamic activity in preclinical models including some of the challenges that had to be overcome during the course of optimization that led to the discovery of MK-2947.

Soluble guanylate cyclase stimulators for cardiovascular disease

254th National Meeting (2017)

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