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

Abstract

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.

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

“…1) was previously marketed under the trademark itramin tosylate® and Nilatil® in Sweden and some other European countries in the 1960s [13,14] and seems to be activated in a different way other than nitroglycerin, thereby inducing less side effects [15]. This was also shown in previous studies of our group, where AEN was covalently linked to valsartan, cilostazol, and pioglitazone and these hybrid molecules showed no signs of in vivo nitrate tolerance but only minor side effects such as in vitro tolerance and oxidative stress [16,17]. …”

“…As we have extensively discussed in our previous reports on AEN-hybrid molecules [16,17], the observed shift to the right of the concentration-relaxation curves might not be related to true in vitro tolerance (tachyphylaxis) but rather be a consequence of impaired phenylephrine-induced vasoconstriction in repeated experiments. A similar observation was made in the present study and phenylephrine-induced vasoconstriction was clearly impaired in repeated challenges with the same drugs in the order cilostazol = cilostazol + CLC-1011 > CLC-1011 = metoprolol + CLC-1011 > valsartan + CLC-1011 > metoprolol = ISDN > DMSO = valsartan = ISMN (Fig.…”

“…To this end, we have used specific organic nitrate linkers to attach an •NO-donating moiety (AEN) to well-established cardiovascular compounds [17]. Since bioactivation of the linker molecules may complicate the release of •NO by these hybrid molecules, we decided to test fixed-dose combinations in the present study.…”

Pharmacological Treatment and Prevention of Cerebral Small Vessel Disease: A Review of Potential Interventions

“…Alternatively, hybrid drugs that comprise a NO donor and cAMP modulator might be relevant, e.g. cilostazol dinitrate . It is conceivable that some treatment strategies might have differential effects on the various types of SVD; whilst BP lowering might be beneficial on all, statins and antiplatelets might be beneficial in reducing lacunar stroke but increase symptomatic bleeding from micro‐bleeds due to their antithrombotic activity. This emphasizes the need to monitor all features of SVD in future trials.…”

In vitro and in vivo Characterization of a New Organic Nitrate Hybrid Drug Covalently Bound to Pioglitazone

“…To this end, we have used specific organic nitrate linkers to attach an NO-donating moiety to well-established cardiovascular compounds (the base compound, e.g. valsartan or cilostazol) [12]. Since the mechanism of action of the base compound does not rely directly on the NO pathway, the resulting compound is a new molecular entity with a dual mode of action.…”