Bioorganic & medicinal chemistry letters · 2012
Discovery of N-[[1-[2-(tert-butylcarbamoylamino)ethyl]-4-(hydroxymethyl)-4-piperidyl]methyl]-3,5-dichloro-benzamide as a selective T-type calcium channel (Cav3.2) inhibitor.
СтатьяНазвание и аннотация: Перевод в очереди
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Giordanetto Fabrizio, Wållberg Andreas, Knerr Laurent, Selmi Nidhal, Ullah Victoria, Thorstensson Fredrik, Lindelöf Åsa, Karlsson Staffan, Nikitidis Grigorios, Llinas Antonio, Wang Qing-Dong, Lindqvist Anders, Högberg Got, Lindhardt Emma, Åstrand Annika, Duker Göran
Аннотация
The T-type calcium channel inhibitor Mibefradil was reported to protect the heart from atrial remodeling, a key process involved in the development of atrial fibrillation and arrhythmias. Mibefradil is not a selective T-type calcium channel inhibitor and also affects the function of different ion channels. Our aim was to develop a selective T-type calcium channel inhibitor to validate the importance of T-type-related pharmacology in atrial fibrillation. Structural optimisation of a previously disclosed hit series focussed on minimising exposure to the central nervous system and improving pharmacokinetic properties, while maintain adequate potency and selectivity. This resulted in the design of N-[[1-[2-(tert-butylcarbamoylamino)ethyl]-4-(hydroxymethyl)-4-piperidyl]methyl]-3,5-dichloro-benzamide, a novel, selective, peripherally restricted chemical probe to verify the role of T-type calcium channel inhibition on atrial fibrillation protection.