| Description: |
Vericiguat (BAY1021189) is a potent, orally available and soluble guanylate cyclase stimulator. |
| In Vivo: |
Chronic oral treatment with 3 or 10 mg/kg vericiguat qd results in a significant attenuation of blood pressure increase during the course of the study. However, the overall rise of blood pressure increase is not halted in the 3 and 10 mg/kg treatment groups. Vericiguat treatment at 3 or 10 mg/kg leads to a significant reduction in kidney injury molecule Kim-1 and osteopontin expression which are used as biomarkers for renal injury and dysfunction. Vericiguat results in a significant and dose-dependent increase in survival rates. In the 3 and 10 mg/kg qd treatment groups, the rat survival rate is 70% and 90%, respectively, at the study end[1]. |
| In Vitro: |
Vericiguat (0.01 μM to 100 μM) stimulates recombinant sGC concentration dependently, by 1.7-fold to 57.6-fold. When combined with the NO donor diethylamine/nitric oxide complex (DEA/NO), vericiguat and DEA/NO have a synergistic effect on the enzyme activity over a wide range of concentrations. At highest concentrations of vericiguat (100 μM) and DEA/NO (100 nM), the specific activity of sGC is 341.6-fold above baseline. Vericiguat stimulates the sGC reporter cell line concentration dependently, with an EC50 of 1005±145 nM. Vericiguat inhibits phenylephrine-induced contractions of rabbit saphenous artery rings, rabbit aortic rings, and canine femoral vein rings concentration dependently, with IC50 values of 798, 692, and 3072 nM, respectively. Vericiguat inhibits the U46619-induced contractions of porcine coronary artery rings concentration dependently, with an IC50 of 956 nM[1]. |
| Animal Administration: |
Rats: Rat are randomly allocated to three study groups: placebo (control), 24 low dose, and 24 high dose (3 and 10 mg/kg per day, respectively, administered po by gavage qd). Blood pressure is measured via the tail-cuff method once before the start of the study (day 0) to exclude preexisting differences between the groups and on day 7, 14, and 21. Body weight and survival are assessed on day 1, 8, and 15 and at the study end. At the end of the study (day 22), all animals are anesthetized, blood is collected, and animals are sacrificed; blood is taken in order to assess plasma parameters, and the heart is dissected into the left and right ventricles and is weighed to assess potential heart hypertrophy. Creatinine, urea, and renin activity in plasma are determined after extraction[1]. |
| References: |
[1]. Follmann M, et al. Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure. J Med Chem. 2017 Jun 22;60(12):5146-5161. |
