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Papers of the Week

2022 Jul 19

Bioorg Chem


Discovery of a novel class of benzoxazole derivatives as histamine H receptor ligands for the treatment of neuropathic pain.


Li Z, Xiao X, Xue Y, Zhou H, Huang C, Zhu M, Zhuang T, Chen Y, Huang L
Bioorg Chem. 2022 Jul 19; 127:106039.
PMID: 35872397.


To discover effective analgesics, we summarize the synthesis, optimization, and pharmacological anti-nociceptive effects of a novel series of benzoxazole derivatives targeting H receptor (HR). The new benzoxazoles were assayed in vitro for histamine HR and HR binding affinity. The best compound 8d (2-methyl-6-(3-(4-methylpiperazin-1-yl)propoxy)benzo[d]oxazole) exhibited high affinity for HR (K = 19.7 nM), high selectivity for ten other off-target receptors, and negligible effects on human ether-a-go-go-related gene (hERG, cardiac ion channel). In rodent animals, compound 8d dose-dependently reversed formalin-evoked pain (Phase I, ED = 6.0 mg/kg; Phase II, ED = 7.8 mg/kg) and CCI-induced neuropathic pain (chronic constriction injury, ED = 15.6 mg/kg). Furthermore, compound 8d showed an excellent safety profile in acute toxicity test (LD > 2000 mg/kg) with a therapeutic index (TI = LD/ED) > 250 and showed a desirable drug-like pharmacokinetic profile. Above characteristics indicate that compound 8d represents a promising candidate analgesic for the treatment of neuropathic pain.