• Maree T Smith and Arjun Muralidharan.
• The University of Queensland, Centre for Integrated Preclinical Drug Development , St Lucia Campus, Brisbane, Queensland 4072 , Australia +61 7 33652554 ; +61 7 33467391 ; maree.smith@uq.edu.au.
• Expert Opin. Ther. Targets. 2015 Jan 1;19(1):25-35.

IntroductionNeuropathic pain and chronic inflammatory pain are large unmet medical needs. Over the past two decades, numerous 'pain targets' have been identified for analgesic drug discovery. Despite promising results in rodent pain models, many compounds modulating such targets lacked efficacy in clinical trials. An exception is oral EMA401, a small-molecule angiotensin II type 2 receptor (AT2R) antagonist.Areas CoveredHerein, angiotensin II/AT2R signaling-induced hyperexcitability and abnormal sprouting of cultured dorsal root ganglion neurons, together with radioligand binding, pharmacokinetics, analgesic efficacy and mode of action of small-molecule AT2R antagonists in rodent models of peripheral neuropathic and chronic inflammatory pain, are reviewed. The findings of a successful Phase IIa clinical trial of EMA401 in patients with neuropathic pain are presented in brief.Expert OpinionThe functional importance of angiotensin II/AT2R signaling has remained enigmatic for decades, and there are no clinically available medications that target the AT2R. However, on the basis of preclinical findings and recent clinical trial data showing that the peripherally restricted, small-molecule AT2R antagonist, EMA401, successfully alleviated neuropathic pain in a Phase II clinical trial, the AT2R is receiving considerable attention as a new therapeutic target with human validation for the relief of peripheral neuropathic and chronic inflammatory pain conditions.

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