Synthesis and biological evaluation of oxadiazole derivatives as inhibitors of soluble guanylyl cyclase

Bioorg Med Chem. 2010 Feb;18(3):1288-96. doi: 10.1016/j.bmc.2009.12.027. Epub 2009 Dec 23.

Abstract

Soluble guanylyl cyclase (sGC) is an ubiquitously expressed enzyme that generates the second messenger cGMP and hence, leads to a number of physiological responses including vasodilation, inhibition of platelet aggregation and neurotransmission. Whilst many activating and stimulating modulators of sGC were identified and studied in recent years, only two selective inhibitors are known: ODQ and NS 2028. Furthermore, a synthetic approach to these inhibitors has not been reported yet. Herein, we describe a novel and efficient synthesis of these inhibitors, as well as the preparation of three different classes of NS 2028 analogues. Biological evaluation of this library using rat aortic smooth muscle cells revealed four new compounds with good to moderate sGC inhibitory activity. Our experiments underline the major importance of the oxadiazole ring in ODQ and NS 2028 for the efficiency of this class of inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / cytology
  • Cells, Cultured
  • Cyclic GMP / metabolism
  • Guanylate Cyclase / antagonists & inhibitors*
  • Guanylate Cyclase / metabolism
  • Myoblasts, Smooth Muscle / drug effects
  • Myoblasts, Smooth Muscle / metabolism
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / chemistry*
  • Oxadiazoles / pharmacology*
  • Rats
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Soluble Guanylyl Cyclase

Substances

  • Oxadiazoles
  • Receptors, Cytoplasmic and Nuclear
  • Guanylate Cyclase
  • Soluble Guanylyl Cyclase
  • Cyclic GMP