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Tesi etd-02292008-123650


Thesis type
Tesi di dottorato di ricerca
Author
MARTELLI, ALMA
URN
etd-02292008-123650
Title
Nitric Oxide Releasing Multitarget Drugs
Settore scientifico disciplinare
BIO/14
Corso di studi
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Commissione
Relatore Prof. Calderone, Vincenzo
Parole chiave
  • nitric oxide
  • hybrid drugs
  • cardiovascular drugs
Data inizio appello
11/04/2008;
Consultabilità
completa
Riassunto analitico
In the last few years, the “one-drug-one-target” paradigm has been shelved and numerous multi-target drugs have been projected and synthesised. Such compounds share two (or more) desired pharmacodynamic properties ensured by the presence of overlapping or conjugation of pharmacophores.<br>This strategy has led to the development of important multi-target drugs consisting of pharmacodynamic hybrids obtained by combining a “native” drug with a molecular moiety able to release nitric oxide (NO), with the aim to reduce possible side-effects or improve the therapeutic impact.<br>My PhD work was focused on the design, characterisation and pharmacological evaluation of two main classes of cardiovascular new “hybrid-drug”: the nitrooxy-derivatives of anti-hypertensive drugs such as sartans and the nitrooxy-derivatives of a hypoglycaemic drug such as glibenclamide.<br>The new class of NO-sartans was represented by several dual compounds in which the native drug Losartan or its active metabolite EXP 3174 are linked to a nitric ester by a series of different spacers conveniently designed in order to modulate the NO-release. <br>These drugs underwent a deep pharmacological characterisation on animal models, through an in vitro evaluation of their vasorelaxing, AT1-antagonist, cardioprotective, anti-hypertrophic and anti-platelet properties. Moreover also an in vivo experimental protocol was carried out in order to compare the NO-sartan effect on blood pressure with those of well-known anti-hypertensive drugs.<br>The two nitrooxy-derivatives of the active metabolite of glibenclamide, the 4-trans-hydroxy derivative, underwent an in vitro pharmacological study on animal models focused to demonstrate an additional vasorelaxing NO-mediated effect conferred through the NO-donor moiety. At the same time, these new hybrid molecules were evaluated by an other in vitro experimental protocol on human islets aimed to verify the maintenance of the hypoglycaemic property through the evaluation of the insulinotropic response.<br>
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