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 (IC 50 =12.73 nM) and sodium nitroprusside (IC 50 =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 (IC 50 =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 drugs.