NO donors. Part 16: Investigations on structure–activity relationships of organic mononitrates reveal 2-nitrooxyethylammoniumnitrate as a high potent vasodilator

Koenig, Andreas; Roegler, Carolin; Lange, Kathrin; Daiber, Andreas; Glusa, Erika; Lehmann, Jochen

doi:10.1016/j.bmcl.2007.08.046

Cited by 23 publications

(21 citation statements)

References 20 publications

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“…The pD 2 value of CLC-1011 was at 6.7, which is close to the previously reported pD 2 value of 7.4 for GTN [29] and unusual for a mononitrate. The data clearly indicate the strong vasodilatory potential of CLC-1011 as compared to the low potency nitrates ISMN (pD 2 value of 4.3) and ISDN (pD 2 value of 6.0).…”

Section: Resultssupporting

confidence: 73%

Basic in vitro Characterization of the Vasodilatory Potential of 2-Aminoethyl Nitrate Fixed-Dose Combinations with Cilostazol, Metoprolol and Valsartan

Oelze

Welschof²,

Knorr³

et al. 2017

Pharmacology

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Background/Aims: 2-aminoethyl nitrate (CLC-1011) is a member of the class of organic nitrates that cause vasodilation by the generation of nitric oxide (•NO). These drugs are mainly used for the treatment of angina pectoris and ischemic heart disease. The aim of this study was to characterize the vasodilatory potency of this organic nitrate alone and in combination with clinically established cardiovascular drugs. Methods: Vasodilation by CLC-1011 was tested by isometric tension studies, either alone or combined with cilostazol, valsartan, and metoprolol. Induction of oxidative stress in isolated heart mitochondria was measured by enhanced chemiluminescence. Bioactivation of CLC-1011 in aortic tissue was measured by electron paramagnetic resonance spectroscopy using an iron-based spin trap for •NO. Results: We observed potent vasodilation by CLC-1011 and additive effects for all three drug combinations. In contrast to nitroglycerin (GTN), CLC-1011 did not stimulate mitochondrial oxidative stress. CLC-1011 was bioactivated to •NO in aortic tissue. Conclusion: In summary, the experiments described in this report demonstrate that CLC-1011 does not induce oxidative stress, is a more potent vasodilator than isosorbide-5-mononitrate and dinitrate ISDN, and displays synergistic vasodilation with other cardiovascular drugs. CLC-1011 fixed dose combinations could be used in the management of cardiovascular diseases.

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Section: Resultssupporting

confidence: 73%

Basic in vitro Characterization of the Vasodilatory Potential of 2-Aminoethyl Nitrate Fixed-Dose Combinations with Cilostazol, Metoprolol and Valsartan

Oelze

Welschof²,

Knorr³

et al. 2017

Pharmacology

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“…These results are consistent with previously published reports and reflect the known tendency for increased vasodilatory efficacy with an increasing number of nitrate groups (ISMN < ISDN). All three nitrate linkers induced vasodilation with pD 2 values consistent with their acting as NO-donating organic mononitrates [21]. Linkers CLC-1270 and CLC-1273 had similar pD 2 values of 4.6 and 4.9, respectively ( fig.…”

Section: Vasodilatory Properties Of Organic Nitrate Linkersmentioning

confidence: 51%

“…This linker includes a carbamate structure, which is relatively more reactive than the other linkers and may be important for facilitating the biotransformation of nitrate into NO. In addition, this linker is based on an AEN, which was previously demonstrated to display a superior vasodilatory potency over all known mononitrates [21,23] and represents the organic nitrate moiety of the nitrate hybrid potassium channel opener nicorandil. (see broken lines).…”

Section: Vasodilatory Properties Of Organic Nitrate Linkersmentioning

confidence: 99%

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

et al. 2012

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Background and Purpose: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. With the present studies we synthesized and characterized new organic nitrate hybrid molecules. Compounds CLC-1265 (valsartan mononitrate) and CLC-1280 (valsartan dinitrate) are derivatives of the angiotensin receptor blocker valsartan, with CLC-1265 containing a single organic nitrate linker and CLC-1280 also containing a second, different linker. Compounds CLC-2000 (cilostazol mononitrate) and CLC-2100 (cilostazol dinitrate) are nitrate derivatives of the phosphodiesterase III inhibitor cilostazol. All compounds are designed as hybrid molecules, potentially combining the NO-donating properties of organic nitrates with the AT1-blocking activity of valsartan or the phosphodiesterase-III–inhibiting effect of cilostazol. Experimental Approach: The properties of new drugs were assessed by isometric tension recording, inhibition of platelet aggregation and formation of mitochondrial reactive oxygen and nitrogen species. Key Results: In this report, all new nitrate compounds are shown, in vitro, to induce vasodilation in the range of other, classical organic nitrates, without inducing oxidative stress or classical nitrate tolerance. In addition, the new hybrid nitrate molecules displayed superior antiaggregatory properties over classical mono- and dinitrates. Conclusions and Implications: Our results demonstrate that organic nitrates can be successfully linked to existing therapeutic molecules to create a new class of molecular entities with a potential dual mechanism of action via combining the established pharmacological properties of valsartan or cilostazol with the vasodilating properties of organic nitrates. Future experimental studies have to demonstrate whether the combined action of these compounds translates to superior therapeutic effects.

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“…that more polarity of the NO donor molecules affected systemic blood pressure more and that less polarity of the donor molecules affected exhaled NO more. This novel structure activity comparison approach for organic nitrites might be useful in the future in designing organic nitrites with wanted effects and selectivity as has been suggested for rational design of other classes of compounds [24] and as used to understand important substructures for organic nitrates [25].…”

Section: Discussionmentioning

confidence: 99%

Formation of new bioactive organic nitrites and their identification with gas chromatography–mass spectrometry and liquid chromatography coupled to nitrite reduction

Nilsson

Lundgren²,

Agvald

et al. 2011

Biochemical Pharmacology

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NO donors. Part 16: Investigations on structure–activity relationships of organic mononitrates reveal 2-nitrooxyethylammoniumnitrate as a high potent vasodilator

Cited by 23 publications

References 20 publications

Basic in vitro Characterization of the Vasodilatory Potential of 2-Aminoethyl Nitrate Fixed-Dose Combinations with Cilostazol, Metoprolol and Valsartan

Basic in vitro Characterization of the Vasodilatory Potential of 2-Aminoethyl Nitrate Fixed-Dose Combinations with Cilostazol, Metoprolol and Valsartan

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

Formation of new bioactive organic nitrites and their identification with gas chromatography–mass spectrometry and liquid chromatography coupled to nitrite reduction

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