In Pursuit of an Allosteric Human Tropomyosin Kinase A (h TrkA) Inhibitor for Chronic Pain

Abstract

Human β-nerve growth factor (β-NGF) and its associated receptor, human tropomyosin receptor kinase A (hTrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located hTrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective hTrkA allosteric inhibitor, 1. 1 was shown to be active against the full length hTrkA, showing preferential binding for the inactive kinase, and was confirmed through the X-ray of hTrkA···1 bound complex. 1 was also found to inhibit β-NGF induced neurite outgrowth in rat PC12 cells. Daily oral administration of 1 improved the joint compression threshold of rats injected intra-articularly with monoiodoacetate over a 14-day period. The efficacy of 1 in a relevant chronic pain model of osteoarthritis coupled with in vitro confirmation of target mediation makes allosteric hTrkA inhibitors potential candidates for modulating pain.

Figure 1

Structure and in vitro profile of 1.

Figure 2

Binding mode of 1 (magenta) bound to extended hTrkA kinase domain (PDB code 6PL4).

Scheme 1. . hTrkA···1 Binding Interaction Derived from the Solved X-ray Complex

PDB accession code is 6PL4.

Figure 3

Joint compression threshold (mean ± SEM) over time for qd and BID administration of 1 in a rat MIA model (N = 10 rats/treatment). Animals were injected with MIA on day −14, and treatment with either vehicle or 1 began on day 0 continuing through day 15. Baseline (BL) recordings occurred immediately prior to the AM dose administration. JCTs measured on day 16 occurred 24 h after the last administration of vehicle or 1. Significance of effects of 1 treatment (qd or BID administration) compared to vehicle-treated animals was calculated at each time point using a two-way repeated-measures ANOVA followed by Tukey’s multiple comparisons (*P < 0.05; **P < 0.01).