Voltage-gated sodium channel blocking activity is a characteristic of certain anaesthetic, antiarrythmic, analgesic and antiepileptic drugs. However, many current therapies have mixed modalities, are associated with inconsistent efficacy and are poorly tolerated.  Pathological conditions are often associated with rapid channel firing so compounds which slow channel cycling by preferential inactivated state-dependent binding, offer the opportunity to mediate disease states while interfering minimally with normal physiology.Herein we describe the discovery and profile of state-dependent sodium channel blockers characterised by an embedded benzylglycinamide moiety.  The imposition of specific stereoisomeric and conformational constraints enabled the identification of compounds with enhanced sodium channel selectivities, and modulation of their state-dependent properties.  Structure activity relationships were identified for hERG blockade, and compound classes were discovered with desirable developability characteristics including metabolic stability, brain penetrancy and disease model efficacy.

Structure-activity relationships in constrained benzylglycinamides: A molecular template for the design of state-dependent sodium channel blockers

244th National Meeting (2012)

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