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.

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Giordanetto F, Wallberg A, Knerr L, Selmi N, Ullah V, Thorstensson F, Lindelof A, Karlsson S, Nikitidis G, Llinas A, Wang QD, Lindqvist A, Hogberg G, Lindhardt E, Astrand A, Duker G

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. Epub 2012 Nov 12.

PubMed ID
23200256 [ View in PubMed
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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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MibefradilCytochrome P450 2D6IC 50 (nM)63N/AN/ADetails
MibefradilVoltage-dependent T-type calcium channel subunit alpha-1HIC 50 (nM)1000N/AN/ADetails