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1‐[(Imidazolidin‐2‐yl)imino]‐1 H ‐indoles as new hypotensive agents: synthesis and in vitro and in vivo biological studies
Author(s) -
Kornicka Anita,
Wasilewska Aleksandra,
Sączewski Jarosław,
Hudson Alan L.,
Boblewski Konrad,
Lehmann Artur,
Gzella Karol,
Belka Mariusz,
Sączewski Franciszek,
Gdaniec Maria,
Rybczyńska Apolonia,
Bączek Tomasz
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12846
Subject(s) - indole test , imidazoline receptor , in vivo , chemistry , in vitro , stereochemistry , pharmacology , in silico , biochemistry , biology , microbiology and biotechnology , gene
A series of 1‐[(imidazolidin‐2‐yl)imino]‐1 H ‐indole analogues of hypotensive α 2 ‐AR agonists, 1‐[(imidazolidin‐2‐yl)imino]‐1 H ‐indazoles, was synthesized and tested in vitro for their activities at α 1 ‐ and α 2 ‐adrenoceptors as well as imidazoline I 1 and I 2 receptors. The most active 1‐[(imidazolidin‐2‐yl)imino]‐1 H ‐indoles displayed high or moderate affinities for α 1 ‐ and α 2 ‐adrenoceptors and substantial selectivity for α 2 ‐adrenoceptors over imidazoline‐I 1 binding sites. The in vivo cardiovascular properties of indole derivatives 3 revealed that substitution at C‐7 position of the indole ring may result in compounds with high cardiovascular activity. Among them, 7‐fluoro congener 3g showed the most pronounced hypotensive and bradycardic activities in this experiment at a dose as low as 10 μg/kg i.v. Metabolic stability of the selected compounds of type 3 was determined using both in vitro and in silico approaches. The results indicated that these compounds are not vulnerable to rapid first‐phase oxidative metabolism.