Effective treatment of chronic pain, in particular neuropathic pain, is a significant unmet medical need. Gabapentin and pregabalin are currently two of the most commonly prescribed drugs to treat neuropathic pain. However, both of these drugs have limited efficacy and are associated with dose limiting side-effects, such as dizziness, drowsiness, and fatigue. To look for potential novel therapeutic targets we utilized a mouse gene knock out (KO) approach combined with evaluation of pain behavior. We 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 and had not previously been associated with neuropathic pain. It was found that AAK1 KO mice exhibit reduced pain behavior in the formalin model for persistent pain and a reduced neuropathic pain response (mechanical allodynia) in the Chung model for neuropathic pain without producing motor side effects. AAK1 is found in both Central Nervous System (CNS) and Peripheral Nervous System (PNS), although it was unknown if penetration into the CNS would be required for efficacy. Synthesis and structure-activity relationship (SAR) studies of a series of pyrrolotriazine AAK1 inhibitors led to the identification of BMS-832309, a brain penetrant, AAK1-selective compound and BMS-901715 a non-CNS penetrant, AAK1-selective compound. BMS-832309 was active in both the formalin model and the Chung model, whereas BMS-901715 showed activity in formalin model but not in the Chung model. BMS-832309 provided proof-of-concept demonstrating that CNS penetration is required for efficacy in neuropathic pain models. Recapitulation of the KO phenotype with a small molecule suggests that AAK1 may be a novel target for the treatment of neuropathic pain. The pyrrolotriazine-based chemotype SAR along with the in vitro profile for BMS-832309 and BMS-901715 will be presented.

Pyrrolotriazines as potent inhibitors for a novel serine-threonine kinase for indication of neuropathic pain

252nd National Meeting (2016)

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