5-(4′-Substituted-2′-nitroanilino)-1,2,3-triazoles as new potential potassium channel activators. I

• Published in: European journal of medicinal chemistry Vol. 35; no. 7; pp. 715 - 720
• Main Authors: Biagi, Giuliana, Calderone, Vincenzo, Giorgi, Irene, Livi, Oreste, Scartoni, Valerio, Baragatti, Barbara, Martinotti, Enrica
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Masson SAS 01-07-2000; Elsevier
• Subjects: 1,2,3-triazoles; Animals; Biological and medical sciences; Cardiovascular system; Male; Medical sciences; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Oligonucleotides, Antisense - chemistry; Pharmacology. Drug treatments; potassium channel activators; Potassium Channels - agonists; Rats; Rats, Wistar; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Vasodilator Agents - chemical synthesis; Vasodilator Agents - chemistry; Vasodilator Agents - pharmacology; Vasodilator agents. Cerebral vasodilators; potassium channel activators; 1,2,3-triazoles; Nitro compound; Vasodilator agent; Rat; Nitrogen heterocycle; Rodentia; Smooth muscle; In vitro; Potassium channel agonist; Vertebrata; Mammalia; Amine; Structure activity relation; Animal; Blood vessel; Triazole derivatives; Aorta; Chemical synthesis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/S0223-5234(00)00180-X

By the hypothesised correlation with the large conductance Ca
++-activated potassium channel (BK
Ca) openers NS 004 and NS 1619, bearing a benzimidazolone ring, a series of new 5-(4′-substituted-2′-nitroanilino)-1,2,3-triazoles were synthesised and tested on in vitro isolated vascular preparation. The compounds were prepared starting from the appropriately substituted 2-nitro-phenylazides by 1,3-dipolar cycloaddition reaction to cyanoacetamide and following Dimroth isomerisation of the corresponding 1-arylsubstituted-5-amino-1,2,3-triazoles. The analogous 5-(4′-substituted-2′-amino-anilino)-1,2,3-triazoles were also prepared to assess the role of the nitro group in the pharmacophoric model. Almost all the nitro compounds showed a vasorelaxant activity on endothelium-denuded rat aortic rings with a potency comparable to that recorded for the reference compound NS 1619. Such a vasorelaxing activity was significantly reduced by the increase of the level of membrane depolarisation and by the potassium channel blocker 4-aminopyridine with a pharmacodynamic behaviour consistent with a potassium channel activation.