New Antianginal Nitro Esters with Reduced Hypotensive Activity. Synthesis and Pharmacological Evaluation of 3--2H-1,3-benzoxazin-4(3H)-ones

Article abstract of DOI:10.1021/jm00001a018

New nitro ester 3-<(nitrooxy)alkyl>-2H-1,3-benzoxazin-4(3H)-ones show marked inhibitory activity against ischemia-induced electrocardiographic changes, with only limited systemic hemodynamic effects, and are reported in the present study.These new nitro vasodilators are potent inhibitors of the electrocardiographic T-wave and S-T segment elevation induced by intravenous or intracoronary administration of Arg-vasopressin or methacholine in the anesthetized rat.The most active compounds are up to 300- and 600- fold more potent than glyceryl trinitrate or Nicorandil, respectively.These nitro esters relax in a concentration-dependent manner the isolated rabbit aorta, at higher concentrations (2 - 40-fold) than glyceryl trinitrate, and reduce the mean arterial blood pressure at doses 7 - 300-fold higher than those required by glyceryl trinitrate to exert a similar hypotensive effect.Remarkably, these compounds retain their anti-ischemic and hemodynamic profile after oral (po) administration.These new nitro ester derivatives, endowed with a marked antianginal activity, which is not associated with concurrent and pronounced falls in systemic blood pressure, represent the leads of a new class of selective nitrovasodilators having a preferential action on large coronary vessels, which could be clinically relevant in the treatment of coronary artery diseases.