The discovery and structure–activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles as selective, CNS penetrating H1-antihistamines for insomnia

A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H1-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H1-antihistamines.

Graphical abstractA series of 2-(piperidin-3-yl)-1H-benzimidazoles were identified as selective H1-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed generally improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H1-antihistamines.Figure optionsDownload full-size imageDownload as PowerPoint slide