Table 2.

Pharmacological effects of olinciguat in preclinical models.

Model	Olinciguat dose (mg/kg or mg/kg/day)	Olinciguat concentration (free)z	Blood pressure (mmHg)	Pharmacological effects
Human cellular sGC assay (HEK-293) EC50	n/a	42.7–105 nM	n/a	n/a
Rat vascular smooth muscle proliferation EC50	n/a	22.4–39 nM	n/a	n/a
Human vascular relaxation EC50	n/a	16–38 nM	n/a	n/a
Normotensive rat	10	1.6–3.3 nMa,e	−11b	↑ ΔHR 134 BPM
Spontaneously hypertensive rat	10	1.6–3.3 nMa,e	−26b	↑ ΔHR 86.2 BPM
DSS rat hypertension & heart failure	10	0.22–0.29 nMe	−16c	↓ cardiac hypertrophy ↓ lung weight ↓ NT-proBNP
Post-MI rat heart failure	30	1.6–1.8 nMe	n.d.	↑ ejection fraction (trend)
ZSF1 rat metabolic syndrome and diabetic nephropathy	30	5.1–6.1 nMe	−8d	↓glucose ↓ cholesterol ↓ triglycerides ↓ liver weight ↓ proteinuria ↓ kidney weight ↓ renal histopath
TNFα mouse vascular inflammation model	10	8.2–10.2 nMf	n.d.	↓ sL-selectin ↓ sP-selectin ↓ sE-selectin ↓ sICAM-1

^aConcentration determined from pooled samples from Wistar and SHR. ^bMaximum absolute change in MAP. ^cDifference in MAP between olinciguat-treated and disease control at end of treatment period. ^dDifference in MAP at end of treatment between enalapril+olinciguat 30 mg/kg and enalapril monotherapy groups. ^eFree concentration in rat studies determined by multiplying total plasma concentration by 1.0% free determined in a rat equilibrium plasma protein binding study. ^fFree concentration in mouse determined by multiplying total concentration in plasma by 1.7% free, determined in a mouse equilibrium plasma protein binding assay.