Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.Nav1.7电压门控离子通道（Nav1.7 voltage-gated ion channel）在疼痛信号通路中的作用经遗传学验证后，使其成为新型疼痛治疗药物开发的极具吸引力的靶点。非选择性Nav通道阻滞剂的临床应用常因心血管及中枢神经系统（CNS）不良反应而受到限制。本研究旨在开发具备口服活性、更高选择性及良好成药性的选择性Nav1.7阻滞剂。本文所述研究聚焦于一系列3位及4位取代的吲唑类化合物。对3位取代吲唑的构效关系（SAR, Structure-Activity Relationship）研究得到了化合物7，该化合物在体外与体内均表现出良好活性，但大鼠体内药代动力学特性较差。对4位取代吲唑的优化工作得到了化合物27与48，二者体外与体内活性俱佳，且大鼠药代动力学特征得到显著改善。化合物27和48在急性大鼠单碘乙酸诱导的骨关节炎疼痛模型中均展现出强效活性；而对48的亚慢性给药实验显示，在7天的给药周期内其半数有效浓度（EC50）呈逐步降低的趋势。