New isoxazole derivatives provided with antihypertensive activity.
A series of diazacycloalkane-quinazoline derivatives of isoxazoles were synthesized and tested in order to identify new potent and selective alpha 1-antagonists. A preliminary screening by using in vitro tests such as binding assay (3H-prazosin and 3H-rauwolscine displacement) and analysis of antagonistic activity in isolated rat aorta (norepinephrine-induced response) and in isolated rat vas deferens (clonidine-induced response) indicated that many of these compounds exhibited a good affinity and selectivity towards alpha 1-adrenergic receptors associated with potent pharmacological activity. In particular, a 3-bromo-5-isoxazolecarbonyl derivative, selected for further in vivo investigation, was provided with as high antihypertensive action as prazosin in spontaneously hypertensive rats (SHR) coupled to a shallow dose-response curve by oral route. Moreover, a higher ratio between oral antihypertensive doses in SHR and normotensive rats was found with respect to reference compound prazosin.
Zambon Group Research Laboratories, Bresso/Milan, Italy.
A
A
Carenzi
D
D
Chiarino
M
M
Napoletano
A
A
Reggiani
A
A
Sala
R
R
Sala
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis; D001013:Aorta, Thoracic / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003000:Clonidine / Q000494:pharmacology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY; D014649:Vas Deferens / Q000187:drug effects; D015016:Yohimbine / Q000378:metabolism
D000959:Antihypertensive Agents; D007555:Isoxazoles; D010080:Oxazoles; D015016:Yohimbine; D003000:Clonidine; D009638:Norepinephrine; D011224:Prazosin