In a preliminary work, we reported two NO-sartans, possessing the characteristics of an AT(1) antagonist and a "slow NO donor", obtained by adding NO-donor side chains to losartan 1. The NO release from an NO-sartan should be modulated in order to strengthen the antihypertensive activity of the native drug and to ensure additional effects, such as the antiplatelet and anti-ischemic ones. To obtain a collection of prototypical NO-sartans, showing different rates of NO release, new NO-donor moieties have been linked to 1 or its active metabolite 2 (EXP 3174). Almost all the synthesized compounds exhibited both AT(1)-antagonist and NO-mediated vasorelaxing properties, with a wide range of NO-releasing rates. Further pharmacological investigation on compound 4a showed that it possessed antihypertensive and cardiac antihypertrophic effects similar to those of the reference AT(1)-blocking or ACE-inhibiting drugs. Furthermore, the additional anti-ischemic cardio-protective properties and antiplatelet effects of 4a have been preliminarily investigated.

New NO-Releasing Pharmacodynamic Hybrids of Losartan and Its Active Metabolite: Design,Synthesis, and Biopharmacological Properties

BRESCHI, MARIA CRISTINA;CALDERONE, VINCENZO;DIGIACOMO, MARIA;MACCHIA, MARCO;MARTELLI, ALMA;MARTINOTTI, ENRICA;MINUTOLO, FILIPPO;RAPPOSELLI, SIMONA;ROSSELLO, ARMANDO;TESTAI, LARA;BALSAMO, ALDO
2006

Abstract

In a preliminary work, we reported two NO-sartans, possessing the characteristics of an AT(1) antagonist and a "slow NO donor", obtained by adding NO-donor side chains to losartan 1. The NO release from an NO-sartan should be modulated in order to strengthen the antihypertensive activity of the native drug and to ensure additional effects, such as the antiplatelet and anti-ischemic ones. To obtain a collection of prototypical NO-sartans, showing different rates of NO release, new NO-donor moieties have been linked to 1 or its active metabolite 2 (EXP 3174). Almost all the synthesized compounds exhibited both AT(1)-antagonist and NO-mediated vasorelaxing properties, with a wide range of NO-releasing rates. Further pharmacological investigation on compound 4a showed that it possessed antihypertensive and cardiac antihypertrophic effects similar to those of the reference AT(1)-blocking or ACE-inhibiting drugs. Furthermore, the additional anti-ischemic cardio-protective properties and antiplatelet effects of 4a have been preliminarily investigated.
Breschi, MARIA CRISTINA; Calderone, Vincenzo; Digiacomo, Maria; Macchia, Marco; Martelli, Alma; Martinotti, Enrica; Minutolo, Filippo; Rapposelli, Simona; Rossello, Armando; Testai, Lara; Balsamo, Aldo
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/198984
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