Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery.

BACKGROUND/AIMS: 5-Ketoximeisosorbide-2-mononitrate (50-IS-2-MN) was synthesized and its pharmacological and toxicological characteristics were examined and compared with its parent drug, isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate. METHODS: Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 50-IS-2-MN and 20-IS-5-MN. RESULTS: After a phenylephrine-induced contraction, 50-IS-2-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of the vascular endothelium. In preparations with or without endothelium, 50-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 50-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10(-5) mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 5O-IS-2-MN and 20-IS-5-MN was greater than 1000 mg/kg. CONCLUSION: These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery.

[Synthesis and cardioprotective effect of a novel anti-ischemic/reperfused injury compound].

The aim of present study is to investigate the cardioprotective effect of a new compound acetyl ferulaic isosorbide (AFI), composed of ferulaic acid (FA) and isosorbide mononitrate (ISMN) by esterification in myocardial ischemia/reperfusion (MI/R). Male Sprague-Dawley rats, subjected to 30 minutes of myocardial ischemia and 3 hours of reperfusion, randomly received one of the following treatments separately: SHAM, I/R (MI/R + solvent), SF (MI/R+SF, 40 mg x kg(-1), ig), ISMN (MI/R + ISMN, 30 mg x kg(-1), ig), SF + ISMN (MI/R + SF + ISMN, 40 mg x kg(-1) + 30 mg x kg(-1), ig) and AFI (MI/R + AFI, 10 mg x kg(-1), ig). Left ventricle developed pressures (LVDP) and the maximal first derivative of developed pressure ( +/-dP / dtmax) were monitored throughout the experiments. Myocardial infarction size, serum creatine kinase (CK) activity, lactate dehydrogenase (LDH) activity, superoxide dismutase (SOD) activity, hydrogen peroxide (H2O2), malondialdehyde (MDA) and nitric oxide (NO) production were determined at the end of reperfusion. Compared with SF, ISMN or SF + ISMN treatment groups, AFI treatment decreased infarction size (n=8, P < 0.01), improved cardiac function as evidenced by increased LVDP and +/- dP/dtmax (n=8, P < 0.05), increased serum SOD activity, reduced serum CK and LDH activities, H2O2 and MDA production (n=8, P < 0.05). The new compound AFI showed a stronger cardioprotective effect against MI/R injury than SF, ISMN or their combined administration did.

Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug.

The transformation of isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) to the corresponding keto derivative and its ketoxime (oxime-nitrate derivative of isosorbide) is described. The effects of IS-5-MN and the new oxime-nitrate (ON) on the endothelial and smooth muscle cells of isolated rings of the rat superior mesenteric artery were examined. After contraction induced by phenylephrine, IS-5-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation. Removal of the vascular endothelium strongly potentiated this effect. On the other hand, the new ON (10(-8)-10(-4) mol/l) was a more potent relaxant than the parent drug, but its effect was not dependent on the vascular endothelium. The inhibitory effect of the artery without endothelium to the new ON was more pronounced than that to IS-5-MN. The mechanism of the relaxant effect of the new compound consisted in the liberation of nitric-oxide (NO) which activated guanylate cyclase (GC), upon which accumulation of cyclic guanosine monophosphate (cGMP) occurred, which was the second messenger leading to relaxation. Tolerance to the frequent applications of the new compound was not observed, moreover a slight increase of the effect was detected in comparison with IS-5-MN for which tolerance was observed to a great extent. Clinically, the new ON could be favorable in all types of angina in comparison with the classical IS-5-MN.

Synthesis, hydrolysis kinetics and anti-platelet effects of isosorbide mononitrate derivatives of aspirin.

Two isomeric aspirin derivatives of isosorbide-5-mononitrate (ISMN) were prepared and evaluated as potential mutual prodrugs of aspirin and nitric oxide. The hydrolysis of both compounds was studied in pH 7.4 phosphate buffer solution, buffered alpha-chymotrypsin solution and 10% buffered rabbit plasma. The benzodioxin-4-one derivative was hydrolysed to salicylic acid and ISMN acetate in buffer solution (t(1/2) 32.1 h), 10% buffered rabbit plasma (t(1/2) 25.7 min) and alpha-chymotrypsin (t(1/2) 86.6 min). The carboxylic acid ester derivative ISMNA was hydrolysed via the salicylate ester in buffer solution (t(1/2) 48.5 h) but was rapidly and almost exclusively hydrolysed to aspirin and ISMN in plasma solution (t(1/2) 2.8 min). The hydrolysis appeared to be enzyme mediated as it was suppressed by co-incubation with eserine. ISMNA was evaluated for its ability to inhibit platelet aggregation in rabbit PRP in response to the following agonists: arachidonic acid (AA) (100 microM), ADP (1.2 microM), phorbol ester (0.5 microM), platelet activating factor (PAF) (5 nM) and the thromboxane mimic U46619 (1.5 microM). ISMNA suppressed platelet response to AA at 1 microM whereas 10 microM aspirin showed no inhibitory effects.

1,4:3,6-Dianhydrohexitol nitrate derivatives. I. Synthesis and antianginal activity of alkylpiperazine derivatives.

A series of 5-deoxy-5-(4-substituted piperazin-1-yl)-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared and evaluated for oral anti-ischemic activities. Inhibition of lysine-vasopressin-induced T-wave elevation in the electrocardiogram (ECG) of rats (angina pectoris model) served as a primary assay. Optimum activity was observed for the compounds with the aryl-heteroatom (O,S, or N)-propyl group. Among them, the phenylthiopropyl-substituted compound 13 exhibited the most potent activity. Furthermore, intraduodenal administration (i.d.) of 13 tended to decrease left ventricular end-diastolic pressure (LVEDP) in a propranolol-induced heart failure model (dogs) and showed a potent protective effect against reperfusion arrhythmia in rats. Thus, 13 (KF 14124) is under further study as an orally active nitrate.

1,4:3,6-Dianhydrohexitol nitrate derivatives. II. Synthesis and antianginal activity of aryl- or arylcarbonylpiperazine derivatives.

A series of 5-(4-aryl- or 4-arylcarbonylpiperazin-1-yl)-5-deoxy-1,4: 3,6-dianhydro-L-iditol 2-nitrates was prepared in order to obtain orally active, nitrate-type vasodilators with reduced side effects. Our drug design was based on a small reduction in the lipophilicity compared to that of 5-deoxy-5-[4-(3-phenylthiopropyl)piperazin-1-yl]-1,4: 3,6-dianhydro-L-iditol 2-nitrate (1, KF14124). Compounds 4h (aryl = benzimidazol-2-yl), 4i (arylcarbonyl = nicotinoyl), and 4w (arylcarbonyl = 3-furoyl) showed potent anti-ischemic activity in a lysine-vasopressin-induced angina pectoris model (rats), and their structure-activity relationships are discussed. Compound 4i exhibited potent vasodilation of the coronary artery in anesthetized dogs and also exhibited potent preload reduction in a heart failure model (dogs) as compared with isosorbide dinitrate (2), nicorandil (3), and KF14124 (1). Furthermore, 4i showed much weaker acute lethal toxicity and less central nervous system depression than 1 in mice. Thus, 4i (KW-3196) is under development as a vasodilator and a drug for treating angina pectoris.

New isosorbide 5-mononitrate derivative with hypotensive activity.

Synthesis and pharmacological properties of the 5-fluoro-nicotinic ester with isosorbide-5-mononitrate 3 are reported. The new compound shows an in vitro activity on rabbit aortic helical strips five times higher than isosorbide-5-mononitrate. The hypotensive activity in guinea-pigs of 3 is markedly superior to that of 5-ISMN. In the rat 3 shows a bioavailability and an acute toxicity inferior to those of 5-ISMN after oral administration.

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)