title: Characterization of new organic nitrate hybrid drugs covalently bound to valsartan and cilostazol.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  The properties of new drugs were assessed by isometric tension recording, inhibition of platelet aggregation and formation of mitochondrial reactive oxygen and nitrogen species.
  
  
  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
  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.
authors.affiliation: Kardiologie, II. Medizinische Klinik, Universitätsmedizin der Johannes-Gutenberg-Universität Mainz, Mainz, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Knorr
authors.forename: Michael
authors.initials: M
authors.lastname: Hausding
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schulz
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.forename: Robert
authors.initials: R
authors.lastname: Rümmler
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schuff
authors.forename: Steffen
authors.initials: S
authors.lastname: Daub
authors.forename: Jörg
authors.initials: J
authors.lastname: Schreiner
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.forename: Tommaso
authors.initials: T
authors.lastname: Gori
authors.forename: Karl
authors.initials: K
authors.lastname: Burgin
authors.forename: Dirk
authors.initials: D
authors.lastname: Sartor
authors.forename: Armin
authors.initials: A
authors.lastname: Scherhag
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000818:Animals; D000077407:Cilostazol; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D018384:Oxidative Stress; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D009566:Nitrates; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D014665:Vasodilator Agents; D000068756:Valsartan; D014633:Valine; D000077407:Cilostazol