New antianginal nitro esters with reduced hypotensive activity. Synthesis and pharmacological evaluation of 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones.
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.
Italfarmaco Research Center, Cinisello Balsamo, Milano, Italy.
F
F
Benedini
G
G
Bertolini
R
R
Cereda
G
G
Donà
G
G
Gromo
S
S
Levi
J
J
Mizrahi
A
A
Sala
D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D048588:Benzoxazines; D001794:Blood Pressure / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced; D066298:In Vitro Techniques; D007511:Ischemia / Q000188:drug therapy; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D009566:Nitrates / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D005996:Nitroglycerin / Q000494:pharmacology; D010078:Oxazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity
D048588:Benzoxazines; D009566:Nitrates; D010078:Oxazines; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D005996:Nitroglycerin; C091726:sinitrodil