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

In a preliminary work, we reported two NO−sartans, possessing the characteristics of an AT1 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 AT1-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 AT1-blocking or ACE-inhibiting drugs. Furthermore, the additional anti-ischemic cardio-protective properties and antiplatelet effects of 4a have been preliminarily investigated.