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Synthesis and characterization of NS-2028 analogues

Background

Soluble guanylyl cyclase (sGC) is a ubiquitously expressed enzyme that synthesizes the second messenger cGMP. sGC has low basal activity which can be stimulated several hundred-fold by nitric oxide. Although, many NO activators and stimulators have been described only two chemically related sGC inhibitors exist: ODQ and NS-2028. The use of the above mentioned sGC inhibitors has helped researchers unravel many of the actions of the NO/sGC/cGMP pathway. The mechanism of action of NS-2028 and ODQ is believed to involve oxidation of the heme iron, making sGC unresponsive to NO. The aim of the present work was to sythesize and characterize a number of NS-2028 analogues for their ability to inhibit sGC. To this end 5 such analogues were generated and are shown below in Figure 1.

figure1

Figure 1

Results

Compounds C was as effective and potent as NS-2028, suggesting that substituting the Br atom in position 8 with a bulkier m-trifluoromethylphenyl group does not alter the activity of NS-2028. Compound B that carries a p-methoxyphenyl group in position 8 was as effective NS2028 and ODQ, but was less potent, as it only inhibited SNP-induced cGMP formation by 43% at 0.1 μÌ, compared to >80% observed with ODQ or NS-2028 when used at the same concentration. Compound A that has an expanded oxadiazolo ring was both less potent and less effective in blocking SNP-induced cGMP production. Expanding the oxazin ring to a benzodiazepinone ring resulted in a compound (compound D) with markedly reduced inhibitory activity. Finally, compound E in which the oxadiazolo ring has been converted to a triazolo ring was devoid of any sGC inhibitory activity.

Conclusion

We conclude that the oxadiazolo ring of NS-2028/ODQ is of major importance for the action of this class of inhibitors.

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Correspondence to Anastasia Pyriochou.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Pyriochou, A., Giannis, A. & Papapetropoulos, A. Synthesis and characterization of NS-2028 analogues. BMC Pharmacol 9, P55 (2009). https://doi.org/10.1186/1471-2210-9-S1-P55

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Keywords

  • Oxide
  • Iron
  • Nitric Oxide
  • Inhibitory Activity
  • Basal Activity