Discovery of a novel class of benzoxazole derivatives as histamine H3 receptor ligands for the treatment of neuropathic pain

Abstract

To discover effective analgesics, we summarize the synthesis, optimization, and pharmacological anti-nociceptive effects of a novel series of benzoxazole derivatives targeting H₃ receptor (H₃R). The new benzoxazoles were assayed in vitro for histamine H₃R and H₁R binding affinity. The best compound 8d (2-methyl-6-(3-(4-methylpiperazin-1-yl)propoxy)benzo[d]oxazole) exhibited high affinity for H₃R (K_i = 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, ED₅₀ = 6.0 mg/kg; Phase II, ED₅₀ = 7.8 mg/kg) and CCI-induced neuropathic pain (chronic constriction injury, ED₅₀ = 15.6 mg/kg). Furthermore, compound 8d showed an excellent safety profile in acute toxicity test (LD₅₀ > 2000 mg/kg) with a therapeutic index (TI = LD₅₀/ED₅₀) > 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.

Keywords: Antinociceptive; Benzoxazole derivatives; Histamine H(3) receptors; Neuropathic pain.