1,2,3-Triazol-carboxanilides and 1,2,3-triazol-( N-benzyl)-carboxamides as BK-potassium channel activators. XII

• Published in: European journal of medicinal chemistry Vol. 43; no. 11; pp. 2618 - 2626
• Main Authors: Calderone, Vincenzo, Fiamingo, Francesca Lidia, Amato, Gabriella, Giorgi, Irene, Livi, Oreste, Martelli, Alma, Martinotti, Enrica
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.11.2008; Elsevier
• Subjects: Alkynes - chemistry; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Anilides - chemistry; Animals; Azoles - chemistry; Biological and medical sciences; BK-activator; BK-potassium channel; Chemistry, Medicinal; Life Sciences & Biomedicine; Male; Medical sciences; Miscellaneous; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Potassium Channels - metabolism; Rats; Rats, Wistar; Science & Technology; Structure-Activity Relationship; Triazole-carboxamide; Triazole-carboxanilide; Triazole-carboxamide; BK-activator; Triazole-carboxanilide; BK-potassium channel; BENZOTRIAZOLES; LARGE-CONDUCTANCE; TRIAZOLYL-BENZIMIDAZOLONES; PHARMACOLOGY; CA2+-ACTIVATED K+ CHANNELS; BENZANILIDE DERIVATIVES; BK potassium channel; Five membered ring; Rat; Nitrogen heterocycle; Rodentia; Benzene derivatives; Ionic channel; In vitro; Potassium channel agonist; Vertebrata; Mammalia; Structure activity relation; Chlorine Organic compounds; Animal; Phenols; Affinity; Aorta; Fluorine Organic compounds; Chemical synthesis; Anilide
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2008.02.032

The chemical structures of many synthetic activators of large-conductance calcium-activated potassium channels (BK channels) satisfy a simple pharmacophore model, consisting of two appropriately substituted phenyl rings connected by a linker of a heterogeneous nature. In this paper, a series of new compounds with modifications of the linker portion of the above pharmacophore are described. In particular, in these new derivatives, the linker portion is represented by a 1,2,3-triazole-carboxamide group, which can be viewed as a combination of two different kinds of linker, independently used in previous series of BK-openers: the amide function and the 1,2,3-triazole ring. The overall finding of this study indicated that the triazole-carboxamide derivatives were generally poorly effective and that this structural modification of the linker is deleterious for activity on BK channels. Therefore, it can be hypothesized that the increase of the steric hindrance of the linker and/or the increase of the distance between the two aromatic portions are negative for the interaction with the biological target. ▪