Soluble guanylate cyclase stimulators for the treatment of hypertension: Discovery of MK-2947

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127574. doi: 10.1016/j.bmcl.2020.127574. Epub 2020 Sep 24.

Abstract

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.

Keywords: Heme-dependent sGC stimulators; Hypertension; MK-2947; NO-sGC-cGMP; Nitric oxide; SHR; Soluble guanylate cyclase; cGMP; sGC stimulators.

MeSH terms

  • Antihypertensive Agents / chemistry
  • Antihypertensive Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Hypertension / drug therapy*
  • Molecular Structure
  • Soluble Guanylyl Cyclase / metabolism*
  • Structure-Activity Relationship

Substances

  • Antihypertensive Agents
  • Soluble Guanylyl Cyclase