Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 52, Issue 36, Pages 9442-9462Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201302588
Keywords
drug discovery; guanylate cyclase; medicinal chemistry; riociguat; structural biology
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The vasodilatory properties of nitric oxide (NO) have been utilized in pharmacotherapy for more than 130years. Still today, NO-donor drugs are important in the management of cardiovascular diseases. However, inhaled NO or drugs releasing NO and organic nitrates are associated with noteworthy therapeutic shortcomings, including resistance to NO in some disease states, the development of tolerance during long-term treatment, and nonspecific effects, such as post-translational modification of proteins. The beneficial actions of NO are mediated by stimulation of soluble guanylate cyclase (sGC), a heme-containing enzyme which produces the intracellular signaling molecule cyclic guanosine monophosphate (cGMP). Recently, two classes of compounds have been discovered that amplify the function of sGC in a NO-independent manner, the so-called sGC stimulators and sGC activators. The most advanced drug, the sGC stimulator riociguat, has successfully undergone PhaseIII clinical trials for different forms of pulmonary hypertension.
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