title: The chemistry and biology of soluble guanylate cyclase stimulators and activators.
abstract: The vasodilatory properties of nitric oxide (NO) have been utilized in pharmacotherapy for more than 130 years. 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 Phase III clinical trials for different forms of pulmonary hypertension.
authors: Bayer Pharma Aktiengesellschaft, Global Drug Discovery, Aprather Weg 18a, 42113 Wuppertal, Germany. markus.follmann@bayer.com
authors: Markus
authors: M
authors: Follmann
authors: Nils
authors: N
authors: Griebenow
authors: Michael G
authors: MG
authors: Hahn
authors: Ingo
authors: I
authors: Hartung
authors: Franz-Josef
authors: FJ
authors: Mais
authors: Joachim
authors: J
authors: Mittendorf
authors: Martina
authors: M
authors: Schäfer
authors: Hartmut
authors: H
authors: Schirok
authors: Johannes-Peter
authors: JP
authors: Stasch
authors: Friederike
authors: F
authors: Stoll
authors: Alexander
authors: A
authors: Straub
mesh_terms: D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006801:Humans; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D000071756:Soluble Guanylyl Cyclase
chemical_list: D020536:Enzyme Activators; D011720:Pyrazoles; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; C542595:riociguat
keywords: drug discovery; guanylate cyclase; medicinal chemistry; riociguat; structural biology