History of the synthesis and pharmacology of isosorbide dinitrate.
A major research program in the University of Maryland School of Medicine, Department of Pharmacology, in the 1930s was the preparation of a large number of sugar alcohols and their anhydrides as substitute carbohydrates for diabetic diets. As an outgrowth of this work, many of these polyols were converted to their nitrate esters and investigated for their vasodilating properties. The organic nitrates that were synthesized were examined for their potency, duration of action, and possible therapeutic use. It was demonstrated that, contrary to prior belief, the depressor and vasodilating action was exhibited by their own molecular structure and not through hydrolysis and reduction to nitrite. The search for the finer mechanism(s) of action on the vascular musculature showed that these nitrated polyols and their anhydrides inhibited arterial adenosine triphosphatase, although this enzyme inhibition did not correlate with pharmacologic activity. Today the mechanism of action of these drugs is not clearly understood at the cellular level. The 1,4:3,6-dianhydrosorbitol 2,5-dinitrate (isosorbide dinitrate) was synthesized, studied, and reported in 1940. It appeared to be a useful drug because blood levels of the unhydrolyzed ester were found to persist for long periods of time. Subsequent clinical studies in the 1960s demonstrated its prophylactic value in angina pectoris and its prolonged action as a therapeutic asset. In 1967 the mononitrate was shown to be formed in vivo when the dinitrate was administered orally and has been studied as the possible pharmacodynamically active moiety.(ABSTRACT TRUNCATED AT 250 WORDS)
D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D049673:History, 20th Century; D006801:Humans; D007548:Isosorbide Dinitrate / Q000138:chemical synthesis / Q000266:history / Q000494:pharmacology; D014481:United States
D007548:Isosorbide Dinitrate