Development of Nav1.7 Selective Inhibitors as Pain Therapeutics

Elena Yiannaki^a, Carlos Perez Medina^a,b, Martin Koltzenburg^c, Erik Årstad^a,b
aUCL Department of Chemistry, Gordon Street, WC1H 0AJ; ^b Institute of Nuclear Medicine, University College Hospital, 235 Euston Road, London NW1 2BU, UK; ^c UCL Institute of Neurology, Queen Square. London, WC1N 3BG

Pain affects more than 20% of the population worldwide. Despite many efforts, its efficient treatment remains a great unmet medical challenge. Pain sensations originate in nociceptors. These are peripheral sensory neurons the excitability of which is controlled by voltage gated sodium channels (VGSC, Na_v).¹ To date, nine different VGSC isoforms have been cloned for the mammalian nervous system. Recent pre-clinical and clinical studies validate Na_v1.7 as one of the isoforms with a key role in the pathophysiology of pain.² Currently marketed VGSC blockers non-selectively inhibit all VGSCs meaning low-systematically tolerable doses and hence limited therapeutic potential.

Our studies focus on developing new Na_v1.7 selective inhibitors as the next generation analgesics with improved efficacy and reduced side effect profile. We have discovered a class of compounds that appears to selectively block pain signalling whilst leaving other sensory signalling largely unaffected. Structure-activity relationships are being elucidated via the design, synthesis and the in vitro characterisation of multiple structural analogues. Optimised structures have shown nanomolar activity for Na_v1.7 and exhibit up to 80-fold selectivity amongst other isoforms. Members of the family have been found to selectively block the nociceptor-containing, myelinated C-fibres while leaving the smaller unmyelinated A-fibres, associated with motor control, completely unaffected.

Schematic representation of the sodium channel.

References: ¹Theile, J.W. et al., Frontiers in Pharmacology 2011, 2, 54; ²Amir, R. et al., J. Pain 2006, 7, S1.