title: New NO-releasing pharmacodynamic hybrids of losartan and its active metabolite: design, synthesis, and biopharmacological properties.
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.
authors.affiliation: Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Breschi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.forename: Enrica
authors.initials: E
authors.lastname: Martinotti
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Aldo
authors.initials: A
authors.lastname: Balsamo
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D019808:Losartan / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan