Document Report Card

ID: ALA1146120

Journal: J Med Chem

Title: New NO-releasing pharmacodynamic hybrids of losartan and its active metabolite: design, synthesis, and biopharmacological properties.

Authors: Breschi MC, Calderone V, Digiacomo M, Macchia M, Martelli A, Martinotti E, Minutolo F, Rapposelli S, Rossello A, Testai L, Balsamo A.

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.

CiteXplore: 16610806

DOI: 10.1021/jm0600186