Synthesis and evaluation of aminobenzothiazoles as blockers of N- and T-type calcium channels

Anjali Sairaman; Fernanda Caldas Cardoso; Anjie Bispat; Richard J Lewis; Peter J Duggan; Kellie L Tuck

doi:10.1016/j.bmc.2018.03.031

Synthesis and evaluation of aminobenzothiazoles as blockers of N- and T-type calcium channels

Bioorg Med Chem. 2018 Jul 15;26(11):3046-3059. doi: 10.1016/j.bmc.2018.03.031. Epub 2018 Mar 19.

Authors

Anjali Sairaman¹, Fernanda Caldas Cardoso², Anjie Bispat³, Richard J Lewis², Peter J Duggan⁴, Kellie L Tuck⁵

Affiliations

¹ IITB-Monash Research Academy, Powai, Mumbai 400076, India; Department of Chemistry, IIT Bombay, Mumbai 400076, India; CSIRO Manufacturing, Bag 10, Victoria 3169, Australia; School of Chemistry, Monash University, Victoria 3800, Australia.
² Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
³ CSIRO Manufacturing, Bag 10, Victoria 3169, Australia; School of Chemistry, Monash University, Victoria 3800, Australia.
⁴ CSIRO Manufacturing, Bag 10, Victoria 3169, Australia; School of Chemical and Physical Sciences, Flinders University, South Australia 5042, Australia. Electronic address: peter.duggan@csiro.au.
⁵ School of Chemistry, Monash University, Victoria 3800, Australia. Electronic address: kellie.tuck@monash.edu.

PMID: 29622412
DOI: 10.1016/j.bmc.2018.03.031

Abstract

Both N- and T-type calcium ion channels have been implicated in pain transmission and the N-type channel is a well-validated target for the treatment of neuropathic pain. An SAR investigation of a series of substituted aminobenzothiazoles identified a subset of five compounds with comparable activity to the positive control Z160 in a FLIPR-based intracellular calcium response assay measuring potency at both Ca_V2.2 and Ca_V3.2 channels. These compounds may form the basis for the development of drug leads and tool compounds for assessing in vivo effects of variable modulation of Ca_V2.2 and Ca_V3.2 channels.

Keywords: Benzothiazole; Ca(V)2.2; Ca(V)3.2; N-type calcium channel; Pain; T-type calcium channel.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzimidazoles / chemical synthesis*
Benzimidazoles / chemistry
Benzimidazoles / pharmacology
Benzothiazoles / chemical synthesis*
Benzothiazoles / chemistry
Benzothiazoles / pharmacology
Calcium Channel Blockers / chemical synthesis
Calcium Channel Blockers / chemistry
Calcium Channel Blockers / pharmacology*
Calcium Channels, N-Type / chemistry*
Calcium Channels, N-Type / drug effects
Calcium Channels, T-Type / chemistry*
Calcium Channels, T-Type / drug effects
Cyclopropanes / chemical synthesis*
Cyclopropanes / chemistry
Cyclopropanes / pharmacology
Molecular Structure
Naphthalenes / chemical synthesis*
Naphthalenes / chemistry
Naphthalenes / pharmacology
Piperazines / chemical synthesis
Piperazines / chemistry
Piperazines / pharmacology
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Structure-Activity Relationship

Substances

Benzimidazoles
Benzothiazoles
Calcium Channel Blockers
Calcium Channels, N-Type
Calcium Channels, T-Type
Cyclopropanes
Naphthalenes
Piperazines
Piperidines
Z160
Z944
aminobenzothiazole compound
NNC 55-0396