Discovery of 1H-Imidazo[4,5-b]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 1 from an in-house compound library, iterative optimization resulted in the potent BET inhibitor DDO-8926 with a unique binding mode and a novel chemical structure. DDO-8926 exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that DDO-8926 is a promising agent for the treatment of NP.

Structure-Guided Design and Synthesis of Pyridinone-Based Selective Bromodomain and Extra-Terminal Domain (BET)-First Bromodomain (BD1) Inhibitors

“…Whereas most BD-containing proteins contain only one domain-recognizing KAc, including some epigenetic writer and eraser proteins, the BET family proteins contain two tandem BDs (BD1 and BD2) in the N-terminal region, both of which adopt four antiparallel helices (αZ, αA, αB, and αC) and two loop regions (ZA and BC loops) . Since the discovery of JQ-1 ( 1 ), small molecules with diverse BD-targeting scaffolds have been reported. − BD1 and BD2 domains share a conserved KAc binding pocket and a hydrophobic Trp-Pro-Phe (WPF) shelf; hence, many of these BET inhibitors show similar binding affinities for BD1 and BD2. − Among these “nonselective” BET inhibitors, an impressive number (>20), including GSK762, ABBV075 ( 2 ), OTX-015, and TEN-010, have advanced into clinical trials as potential cancer treatments. However, side effects, notably dose-dependent thrombocytopenia, have limited the progress of these BET inhibitors in clinical studies. , …”