Table 1.

cGMP modulating drugs and drug candidates for SCD therapy.

Classification of agents	Mechanism of action	Agents	Pre-clinical evidence in SCD	Clinical evidence in SCD	Limitations
Nitric oxide donors	Improvement in NO bioavailability.	NO inhalation	Improvement in survival and lung injury following exposure to hypoxia and hypoxia-reperfusion in SCD animal model84,85	Improvement in pain scores during VOC86,87	No effects on Hb oxygen affinity; failure to improve outcomes of VOC compared with placebo; no efficacy for the treatment of ACS84,85,86
		L-arginine supplementation	Increase of NO metabolite levels; reduction of lipid peroxidation; increase of antioxidant levels in SCD animal model88	Benefits on pulmonary hypertension in SCD; amplification of NO response when co-administered with HU; reduction in pain scores and opioid use in children experiencing VOC89–91	Failure to demonstrate long-term clinical efficacy; alterations in redox potential of RBCs; no effects on hospital length of stay during VOC91,92
		Hydroxyurea	Evidence for cGMP-dependent effects:Anti-inflammatory effects via an NO-sGC dependent mechanism in SCD animal model.55 Induction of γ-globin expression in human erythroid progenitor cells via a sGC-dependent pathway60	Evidence for cGMP-dependent effects: Association of RBC HbF with intracellular [cGMP], indicating a role for sGC-mediated elevation of HbF; increase of plasma NO metabolites and cGMP levels in patients on HU61,77,83	Cytotoxic effects and long-term benefits for chronic organ damage still unclear70,71
		Nitrite	Improvement in SCD RBC deformability in vitro; reductions in RBC, leukocyte and platelet adhesion; reduction in hemolysis rate in vitro and in SCD mice93	Increase in regional blood flow in patients with SCD in steady state94	Reduced vasodilatory sensitivity in SCD individuals, compared with those without SCD94
sGC stimulators	Elevation of cGMP by sGC in a heme-dependent manner.	BAY 41-2272	Reduction of SCD neutrophil adhesion in vitro; improvement of cavernosal relaxation in SCD animal model95,96	No clinical studies for SCD.	Unsuitable for clinical use: Low metabolic stability; low oral bioavailability97
		Riociguat (BAY 63-2521)	No pre-clinical studies for SCD.	Safe and well tolerated, in SCD patients with chronic thromboembolic pulmonary hypertension: Significant improvements in exercise capacity, NT-proBNP, and RVSP in some of the treated patients98	Short half-life in humans and requires thrice-daily dosing;99 potential hypotensive effects should be monitored in SCD.
		Vericiguat (BAY 102-1189)	No pre-clinical studies for SCD.	No clinical studies for SCD.	Not applicable.
		Olinciguat (IW-1701)	Induces in vitro expression of γ-globin gene in erythroleukemic. Cells decreases leukocyte recruitment in C57BL/6 mice following an inflammatory stimulus100,101	Phase 2 double-blind, placebo-controlled multi-site trial for use in SCD currently undergoing (NCT03285178). Results not yet available.	Not yet reported.
sGC activators	Production of cGMP by increasing oxidized sGC activity in a heme-independent manner.	BAY 54-6544	Decreases cardiac remodeling and increases vaso-relaxation in SCD animal model102	No clinical studies for SCD.	Not applicable.
		BAY 60-2770	Decreases adhesive properties of human SCD neutrophils in vitro; decreases leukocyte recruitment and vaso-occlusive processes in SCD animal model103	No clinical studies for SCD.	Not applicable.
Phosphodiesterase inhibitors	Prevention of intracellular cGMP degradation.	Sildenafil	Beneficial effects on priapism in SCD animal models104	Prevention and resolution of recurrent ischemic episodes of priapism in SCD105,106A clinical trial (NCT00492531) to evaluate the effects of sildenafil in subjects with SCD with high TRV was terminated early due to increased hospitalizations for pain in patients on sildenafil; no favorable effects on the evaluated parameters were observed107	Risk of augmented pain processing107
		BAY 73-6691	Decrease of in vitro adhesive properties of SCD neutrophils. Inhibition of leukocyte recruitment, vaso-occlusive processes and survival in SCD animal model95,108,109	No clinical studies in humans.	Not applicable.
			Reduction of leukocyte-platelet aggregates and endothelial activation in SCD animal model110	A phase 1 clinical trial (NCT02114203) has been conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics in subjects with SCD. Soluble E-selectin and heterocellular aggregates reportedly decreased in patients on PF-04447943.111 Apparent overall safety observed, although adverse events were observed in 3 out of 22 patients on PF-04447943 (vaso-occlusive crisis, biliary colic and pneumonia).	Not yet reported.
		IMR-687	Inhibition of microvascular stasis following hypoxia; increase in RBC HbF content; decrease in RBC sickling and leukocytosis in SCD animal model112	A randomized, placebo-controlled, multicenter study phase 2 trial (NCT03401112) to determine the safety, pharmacokinetics, and preliminary pharmacodynamics of escalating doses of IMR-687 in patients with SCD is underway. Results not yet available.	Not yet reported.

HU; hydroxyurea: NO; nitric oxide; NT-proBNP; N-terminal pro-brain natriuretic peptide: RBC; red blood cell: RVSP; right ventricular systolic pressure: SCD; sickle cell disease: TRV; ricuspid regurgitant velocity.