title: Synthesis and vasodilatory activity of new N-acylhydrazone derivatives, designed as LASSBio-294 analogues.
abstract: Conventional therapy to treat hypertension often involves arterial vasodilation. Decrease of blood pressure by vasodilators is normally associated with adverse effects because of their low vascular selectivity. This is of interest to develop new molecules with potential for clinical use and fewer side effects. Recently, a new bioactive compound of the N-acylhydrazone class, LASSBio-294, was shown to produce a cardioinotropic effect and vasodilation. In this report, new derivatives of LASSBio-294 were designed and tested on the contractile response of vascular smooth muscle from Wistar rats. Phenylephrine-induced contracture in the aorta was inhibited by the derivatives LASSBio-785 and LASSBio-788. The concentrations necessary to cause 50% reduction of the maximal vascular response (IC50) were 10.2 +/- 0.5 and 67.9 +/- 6.5 microM. Vasodilation induced by both derivatives is likely to be mediated by a direct effect on smooth muscle because it was not dependent on the integrity of vascular endothelium. LASSBio-785 was seven times more potent than the reference compound LASSBio-294 (IC50 = 74 microM) in producing an endothelium-independent vasodilator effect.
authors.affiliation: Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, RJ 21941-590, Brazil.
authors.forename: Alexandre G
authors.initials: AG
authors.lastname: Silva
authors.forename: Gisele
authors.initials: G
authors.lastname: Zapata-Sudo
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Kummerle
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Sudo
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects*; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010656:Phenylephrine / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D006835:Hydrazones; C439284:LASSBio 294; C503362:LASSBio-785; C503361:LASSBio-788; D013876:Thiophenes; D014665:Vasodilator Agents; D010656:Phenylephrine