title: 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.
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.
authors.affiliation: Medicinal Chemistry, AstraZeneca R&D CVGI iMed, Pepparedsleden 1, SE-431 83 Mölndal, Sweden. fabrizio.giordanetto@astrazeneca.com
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.forename: Andreas
authors.initials: A
authors.lastname: Wållberg
authors.forename: Laurent
authors.initials: L
authors.lastname: Knerr
authors.forename: Nidhal
authors.initials: N
authors.lastname: Selmi
authors.forename: Victoria
authors.initials: V
authors.lastname: Ullah
authors.forename: Fredrik
authors.initials: F
authors.lastname: Thorstensson
authors.forename: Åsa
authors.initials: Å
authors.lastname: Lindelöf
authors.forename: Staffan
authors.initials: S
authors.lastname: Karlsson
authors.forename: Grigorios
authors.initials: G
authors.lastname: Nikitidis
authors.forename: Antonio
authors.initials: A
authors.lastname: Llinas
authors.forename: Qing-Dong
authors.initials: QD
authors.lastname: Wang
authors.forename: Anders
authors.initials: A
authors.lastname: Lindqvist
authors.forename: Got
authors.initials: G
authors.lastname: Högberg
authors.forename: Emma
authors.initials: E
authors.lastname: Lindhardt
authors.forename: Annika
authors.initials: A
authors.lastname: Åstrand
authors.forename: Göran
authors.initials: G
authors.lastname: Duker
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D020747:Calcium Channels, T-Type / Q000737:chemistry* / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; C037689:benzamide