title: Successful reduction of off-target hERG toxicity by structural modification of a T-type calcium channel blocker.
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.
authors.affiliation: Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Yeon Jae
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do 420-743, Republic of Korea.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do 420-743, Republic of Korea. Electronic address: kyejung@catholic.ac.kr.
authors.forename: Kye Jung
authors.initials: KJ
authors.lastname: Shin
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry; D000588:Amines / Q000737:chemistry; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D020747:Calcium Channels, T-Type / Q000187:drug effects; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D051381:Rats
chemical_list: D000577:Amides; D000588:Amines; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D000644:Quaternary Ammonium Compounds
keywords: L-type calcium channel; Pharmacokinetics; T-type calcium channel blocker; hERG