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Medicinal Chemistry and Therapeutic Applications of the Gasotransmitters NO, CO, and H2S and their Prodrugs

Pulmonary, Bone, Vitamins and Autocoid Therapeutic Agents

  1. Csaba Szabo1,2

Published Online: 29 JAN 2010

DOI: 10.1002/0471266949.bmc178

Burger's Medicinal Chemistry and Drug Discovery

Burger's Medicinal Chemistry and Drug Discovery

How to Cite

Szabo, C. 2010. Medicinal Chemistry and Therapeutic Applications of the Gasotransmitters NO, CO, and H2S and their Prodrugs. Burger's Medicinal Chemistry and Drug Discovery. 265–368.

Author Information

  1. 1

    Ikaria, Inc., Seattle, WA

  2. 2

    University of Texas Medical Branch, Department of Anesthesiology, Galveston, TX

Publication History

  1. Published Online: 29 JAN 2010

Abstract

Nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S) are the main endogenous gasotransmitters. These gases are produced by the body by enzymatic reactions and serve physiological regulatory purposes including vasodilatation and anti-inflammatory effects. Over the past decades, multiple approaches have been identified for the therapeutic exploitation of these three gasotransmitters, based on inhalation of the gases and/or the parenteral or enteral administration of various formulations of these molecules or their prodrugs. Here we overview the medicinal chemistry and the therapeutic applications of NO, CO, and H2S and their prodrugs. Inhaled NO is used clinically to selectively dilate the pulmonary vasculature in the therapy of the primary pulmonary hypertension of the newborn. Organic nitrates such as glyceryl trinitrate or nitroglycerin are used in the therapy of acute and chronic angina. Sodium nitroprusside is used to counteract acute hypertensive crisis. Another class of clinical-stage NO donor drugs is the sydnonimines (molsidomine, linsidomine). Additional classes of NO donors include diazeniumdiolates (NONOates) and S-nitrosothiols, with beneficial effects in various preclinical models of disease. With respect to CO, the main therapeutic approaches are CO inhalation (currently in clinical trials for the experimental therapy of delayed graft function associated with kidney transplantation) and carbon monoxide releasing compounds of various classes (in preclinical stage). With respect to H2S, a parenteral injectable formulation of the gas is currently is Phase I trials. Several classes of H2S donor molecules have also been identified, which are used in preclinical studies.

Keywords:

  • blood vessels;
  • carbon monoxide;
  • cell death;
  • critical care;
  • endothelial dysfunction;
  • heme oxygenase;
  • hydrogen sulfide;
  • mitochondria;
  • nitric oxide;
  • nitroglycerin;
  • nitrosothiols;
  • nitrovasodilatators;
  • oxidative stress;
  • peroxynitrite;
  • superoxide;
  • pulmonary hypertension;
  • reperfusion injury;
  • vascular tone;
  • vasodilatation