2. Academic Validation
  3. 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

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

Affiliation

  • 1 Medicinal Chemistry, AstraZeneca R&D CVGI iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. fabrizio.giordanetto@astrazeneca.com
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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