Referenced in: none

Automatically associated channels: Kv11.1

Title: Successful reduction of off-target hERG toxicity by structural modification of a T-type calcium channel blocker.

Authors: Yeon Jae Choi, Jae Hong Seo, Kye Jung Shin

Journal, date & volume: Bioorg. Med. Chem. Lett., 2014 Feb 1 , 24, 880-3

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24412109

Abstract
To obtain an optimized T-type calcium channel blocker with reduced off-target hERG toxicity, we modified the structure of the original compound by introducing a zwitterion and reducing the basicity of the nitrogen. Among the structurally modified compounds we designed, compounds 5 and 6, which incorporate amides in place of the original compound's amines, most appreciably alleviated hERG toxicity while maintaining T-type calcium channel blocking activity. Notably, the benzimidazole amide 5 selectively blocked T-type calcium channels without inhibiting hERG (hERG/T-type⩾220) and L-type channels (L-type/T-type=96), and exhibited an excellent pharmacokinetic profile in rats.