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 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 C
MC
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Calderone
Vincenzo
V
Digiacomo
Maria
M
Macchia
Marco
M
Martelli
Alma
A
Martinotti
Enrica
E
Minutolo
Filippo
F
Rapposelli
Simona
S
Rossello
Armando
A
Testai
Lara
L
Balsamo
Aldo
A
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
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D044140:Receptor, Angiotensin, Type 1; D019808:Losartan