NO-independent, haem-dependent soluble guanylate cyclase stimulators

Handb Exp Pharmacol. 2009;(191):277-308. doi: 10.1007/978-3-540-68964-5_13.

Abstract

The nitric oxide (NO) signalling pathway is altered in cardiovascular diseases, including systemic and pulmonary hypertension, stroke, and atherosclerosis. The vasodilatory properties of NO have been exploited for over a century in cardiovascular disease, but NO donor drugs and inhaled NO are associated with significant shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and non-specific effects such as post-translational modification of proteins. The development of pharmacological agents capable of directly stimulating the NO receptor, soluble guanylate cyclase (sGC), is therefore highly desirable. The benzylindazole compound YC-1 was the first sGC stimulator to be identified; this compound formed a lead structure for the development of optimized sGC stimulators with improved potency and specificity for sGC, including CFM-1571, BAY 41-2272, BAY 41-8543, and BAY 63-2521. In contrast to the NO- and haem-independent sGC activators such as BAY 58-2667, these compounds stimulate sGC activity independent of NO and also act in synergy with NO to produce anti-aggregatory, anti-proliferative, and vasodilatory effects. Recently, aryl-acrylamide compounds were identified independent of YC-1 as sGC stimulators; although structurally dissimilar to YC-1, they have a similar mode of action and promote smooth muscle relaxation. Pharmacological stimulators of sGC may be beneficial in the treatment of a range of diseases, including systemic and pulmonary hypertension, heart failure, atherosclerosis, erectile dysfunction, and renal fibrosis. An sGC stimulator, BAY 63-2521, is currently in clinical development as an oral therapy for patients with pulmonary hypertension. It has demonstrated efficacy in a proof-of-concept study, reducing pulmonary vascular resistance and increasing cardiac output from baseline. A full, phase 2 trial of BAY 63-2521 in pulmonary hypertension is underway.

Publication types

  • Review

MeSH terms

  • Acrylamides / pharmacology
  • Animals
  • Cardiovascular Diseases / drug therapy
  • Cardiovascular Diseases / physiopathology
  • Clinical Trials as Topic
  • Enzyme Activators / pharmacology*
  • Guanylate Cyclase / drug effects*
  • Guanylate Cyclase / metabolism
  • Heme / metabolism*
  • Humans
  • Indazoles / pharmacology
  • Nitric Oxide / metabolism
  • Pyrimidines / pharmacology
  • Receptors, Cytoplasmic and Nuclear / drug effects*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Signal Transduction
  • Soluble Guanylyl Cyclase

Substances

  • Acrylamides
  • Enzyme Activators
  • Indazoles
  • Pyrimidines
  • Receptors, Cytoplasmic and Nuclear
  • Nitric Oxide
  • Heme
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase