Effective treatment of chronic pain, in particular neuropathic pain, is a significant unmet medical need. Current standard of care compounds have limited efficacy and are often associated with dose limiting side-effects, such as dizziness, drowsiness, and fatigue. We recently identified adaptor associated kinase 1 (AAK1), also known as AP2-associated protein kinase 1, as a potential novel therapeutic target for neuropathic pain. AAK1 is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 had not previously been associated with neuropathic pain. It was found that AAK1 knock-out mice exhibit reduced pain behavior in the formalin assay for persistent pain and a reduced neuropathic pain response (mechanical allodynia) in the Chung model for neuropathic pain without producing motor side effects. This presentation will cover the discovery, synthesis, and in vivo evaluation of AAK1 inhibitors in the benzo[c][2,7]naphthyridin-5(6H)-one and 5H-chromeno[3,4-c]pyridine class.

Benzo[c][2,7]naphthyridin-5(6H)-one and 5H-chromeno[3,4-c]pyridine as potent inhibitors of a novel serine/threonine kinase for the potential treatment of neuropathic pain

254th National Meeting (2017)

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