Olinciguat, an Oral sGC Stimulator, Exhibits Diverse Pharmacology Across Preclinical Models of Cardiovascular, Metabolic, Renal, and Inflammatory Disease

Abstract

Nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic 3',5' GMP (cGMP) signaling plays a central role in regulation of diverse processes including smooth muscle relaxation, inflammation, and fibrosis. sGC is activated by the short-lived physiologic mediator NO. sGC stimulators are small-molecule compounds that directly bind to sGC to enhance NOmediated cGMP signaling. Olinciguat, (R)-3,3,3-trifluoro-2-(((5-fluoro-2-(1-(2fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-4-yl)amino)methyl)-2hydroxypropanamide, is a new sGC stimulator currently in Phase 2 clinical development. To understand the potential clinical utility of olinciguat, we studied its pharmacokinetics, tissue distribution, and pharmacologic effects in preclinical models. Olinciguat relaxed human vascular smooth muscle and was a potent inhibitor of vascular smooth muscle proliferation in vitro. These antiproliferative effects were potentiated by the phosphodiesterase 5 inhibitor tadalafil, which did not inhibit vascular smooth muscle proliferation on its own. Olinciguat was orally bioavailable and predominantly cleared by the liver in rats. In a rat whole body autoradiography study, olinciguat-derived radioactivity in most tissues was comparable to plasma levels, indicating a balanced distribution between vascular and extravascular compartments. Olinciguat was explored in rodent models to study its effects on the vasculature, the heart, the kidneys, metabolism, and inflammation. Olinciguat reduced blood pressure in normotensive and hypertensive rats. Olinciguat was cardioprotective in the Dahl rat salt-sensitive hypertensive heart failure model. In the rat ZSF1 model of diabetic nephropathy and metabolic syndrome, olinciguat was renoprotective and associated with lower circulating glucose, cholesterol, and triglycerides. In a mouse TNFa-induced inflammation model, olinciguat treatment was associated with lower levels of endothelial and leukocyte-derived soluble adhesion

Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies

“…Moreover, intravenous doses of 100 µg/kg of BAY 41-2272 significantly decrease blood pressure in anesthetized rats ( Straub et al, 2002 ), whereas in conscious rats, both BAY412272 and BAY60-2770, when given intravenously (300 µg/kg), are reported to have no significant effect on blood pressure ( Fullhase et al, 2015 ). Olinciguat, another sGC stimulator, which is currently in phase 2 clinical development for use in patients with sickle cell anemia (NCT03285178) ( Zimmer et al, 2020 ), not only reduces blood pressure in humans and in hypertensive and normotensive rats but also successfully reduces inflammatory mechanisms in TNF-stimulated mice ( Buys et al, 2018 ; Zimmer et al, 2020 ). As such, further preclinical and clinical studies should be careful to evaluate the extent of any effect of sGC agonists on blood pressure when considering the use of these agents for the treatment of SCA.…”

Current and novel therapies for the prevention of vaso-occlusive crisis in sickle cell disease

“…76 cGMP production is regulated by nitric oxide binding to soluble guanylate cyclase. 16,77 As already discussed, cell-free hemoglobin and arginase I reduce nitric oxide, resulting in endothelial dysfunction. 13,15,16 As a result, decreased nitric oxide may result in reduced cGMP.…”

Nitric oxide and sickle cell disease—Is there a painful connection?

“…One must also consider the possibility that the effect of given treatments on frequency and hospital course of acute pain crises may not inform or predict the effects of those treatments on other complications of SCD. Nevertheless, while strategies to increase NO donation/nitrite supplementation may not be suitable approaches for SCD, it is worth noting that other phosphodiesterase inhibitors (phosphodiesterase-9) and cGMP amplifying agents are currently under various stages of investigation for the treatment of vascular SCD complications 94–96. Whether these agents will have a role in acute pain crises or chronic pain in SCD is yet unknown.…”