The discovery of novel 3-aryl-indazole derivatives as peripherally restricted pan-Trk inhibitors for the treatment of pain

[Display omitted] •New 3-aryl-indazole derivatives as pan-Trk inhibitors were designed and synthesized.•Substrates for efflux transporter were explored by the Caco-2 assay.•Membrane permeability was increased by lowing basicity.•17c demonstrated restricted brain penetration and good in vivo efficacy in a CFA-induced thermal hypersensitivity model. The design, synthesis, and biological evaluation of novel 3-aryl-indazole derivatives as peripherally selective pan-Trk inhibitors are described. Three strategies were used to obtain a potent compound exhibiting low central nervous system (CNS) penetration and high plasma exposure: 1) a structure-based drug design (SBDD) approach was used to improve potency; 2) a substrate for an efflux transporter for lowering brain penetration was explored; and 3) the most basic pKa (pKa–MB) value was used as an indicator to identify compounds with good membrane permeability. This enabled the identification of the peripherally targeted 17c with the potency, kinase-selectivity, and plasma exposure required to demonstrate in vivo efficacy in a Complete Freund's adjuvant (CFA)-induced thermal hypersensitivity model.