Discovery of 1<i>H</i>-Imidazo[4,5-<i>b</i>]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain

Abstract

Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit <b>1</b> from an in-house compound library, iterative optimization resulted in the potent BET inhibitor <b>DDO-8926</b> with a unique binding mode and a novel chemical structure. <b>DDO-8926</b> exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, <b>DDO-8926</b> significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that <b>DDO-8926</b> is a promising agent for the treatment of NP.