Renal effects of soluble guanylate cyclase stimulators and activators: A review of the preclinical evidence

Abstract

Direct stimulation of soluble guanylate cyclase (sGC) is emerging as a potential new approach for the treatment of renal disorders. sGC catalyzes the formation of cyclic guanosine monophosphate (cGMP), deficiency of which is implicated in the pathogenesis of chronic kidney disease (CKD). Therefore, new classes of drugs - sGC stimulators and activators - are being investigated in preclinical models under conditions where nitric oxide is deficient. In preclinical models with different etiologies of CKD, the sGC stimulators BAY 41-2272, BAY 41-8543, BAY 60-4552, riociguat and vericiguat and the sGC activators cinaciguat, ataciguat, BI 703704 and GSK2181236A have shown consistently renoprotective effects. Clinical trials are required to confirm these findings in humans, and to ascertain whether these agents could provide a future alternative to guideline-recommended treatments.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…Very few, if any, studies from the pharmaceutical industry on the development on mAC and sAC inhibitors have been published, in marked contrast to the situation regarding allosterically acting NO-dependent sGC stimulators and NO-independent sGC activators (Stasch et al, 2011(Stasch et al, , 2015Friebe et al, 2015). One reason for these differences may be the intrinsic difficulties from the medicinal chemistry perspective.…”

“…The potent sGC inhibition by (M)ANT-nucleotides is not surprising in light of the high conservation of the catalytic domains of these enzymes (Sunahara et al, 1998;Dove et al, 2014). Given the beneficial clinical effects of allosteric sGC activators and sGC stimulators (Stasch et al, 2011(Stasch et al, , 2015, sGC inhibition would be clearly an off-target effect of mAC inhibitors (Dove et al, 2014). However, there is evidence for pharmacological distinction between mACs and sGC with (M)ANT-and TNP-nucleotides (Dove et al, 2014) (Table 6).…”

“…Because of the structural differences between mACs (class IIIa) and sAC (class IIIb) (Linder and Schultz, 2003), the development of global mAC inhibitors and sAC inhibitors with selectivity against the other AC class may be feasible, but crossinhibition of sGC, definitively an off-target effect (Stasch et al, 2011(Stasch et al, , 2015Dove et al, 2014), has to be considered as well. From a medicinal chemistry point-of-view, the development of isoform-selective mAC inhibitors is particularly challenging because of the high degree of conservation of the catalytic core.…”

“…Inhibition of sGC is a problematic property when aiming at the clinical application of mAC and sAC inhibitors (Stasch et al, 2011(Stasch et al, , 2015Dove et al, 2014). Unfortunately, pIC 50 values for sGC of the compounds listed in Table 8 are not yet available.…”

“…In contrast to ACs, the development of drugs targeting sGC and pGCs is much more advanced (Friebe et al, 2015). Specifically, the exploration of allosteric regulatory sites in sGC resulted in the development of potent NO-independent sGC activators (cinaciguat being the prototype) and NO-dependent sGC stimulators (riociguat being the prototype) with many clinical applications (Stasch et al, 2011(Stasch et al, , 2015.…”