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

  • Bioorg Med Chem Lett. 2013 Jan 1;23(1):119-24. doi: 10.1016/j.bmcl.2012.10.140.
Fabrizio Giordanetto  1 ,  Andreas Wållberg ,  Laurent Knerr ,  Nidhal Selmi ,  Victoria Ullah ,  Fredrik Thorstensson ,  Åsa Lindelöf ,  Staffan Karlsson ,  Grigorios Nikitidis ,  Antonio Llinas ,  Qing-Dong Wang ,  Anders Lindqvist ,  Got Högberg ,  Emma Lindhardt ,  Annika Åstrand ,  Göran Duker
Affiliations
  • 1. Medicinal Chemistry, AstraZeneca R&D CVGI iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. [email protected]
PMID: 23200256 DOI: 10.1016/j.bmcl.2012.10.140
Abstract

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.

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