Synthesis and Vasorelaxant Activity of Nitrate−Coumarin Derivatives

Due to the need for new chemical entities for cardiovascular diseases, we have synthesized a new series of nitrate−coumarins and evaluated their vasorelaxant activity in contraction-relaxation studies using rat aorta rings precontracted with phenylephrine or by depolarization with a high concentration of potassium chloride. Four of the new compounds were able to relax smooth vascular muscle with a similar profile and potency to glyceryl trinitrate (IC50=12.73 nM) and sodium nitroprusside (IC50=4.32 nM). Coumarin-7-yl-methyl nitrate (4), the best compound within the series, was able to relax smooth vascular muscle in the low nanomolar range (IC50=1.92 nM). The mechanisms of action have been explored, being the activation of sGC and the opening of K+ channels involved. Our studies indicate that the new nitrate derivatives are reversible and not deleterious for aortic rings, suggesting that these compounds have a potential interest for the development of new and highly efficient vasodilator drugsXunta de Galicia. Grant Number: ED431B 2020/26. Ministerio de Ciencia e Innovación Grant Numbers: PID2020-116076RJ-I00/AEI/10.13039/501100011033, PID2020-119178GB-I00. Fundação para a Ciência e Tecnologia. Grant Numbers: PTDC/ASP-PES/28397/2017, CEECIND/02423/2018, UIDB/00081/2020, LA/P/0056/2020, EXPL/BIA-BQM/0492/2021S