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

Human β-nerve growth factor (β-NGF) and its associated receptor, human tropomyosin receptor kinase A (TrkA), have been demonstrated to be key factors in the perception of pain. However, efficacious small molecule therapies targeting the intracellularly located TrkA kinase have not been explored thoroughly for pain management. Herein, we report the pharmacological properties of a selective TrkA allosteric inhibitor, .

Lead identification and characterization of hTrkA type 2 inhibitors.

Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.

Pharmacological evaluation of a selective bradykinin B antagonist in a canine model of arthritis.

The effects of a selective bradykinin 1 receptor antagonist, compound A, were evaluated in a canine model of acute inflammatory model of arthritis. Despite detection of the B receptor in canine type B synoviocytes using a fluorescent ligand, oral administration of compound A (9 and 27 mg/kg) did not improve weight bearing of dogs injected intra-articularly with IL-1β in a force plate analysis. Analysis of the synovial fluid of IL-1β-treated dogs indicated high levels of bradykinin postchallenge.

Effects of inclusion complexation on the transepithelial transport of a lipophilic substance in vitro.

Poor oral bioavailability of three experimental compounds, 1-III, observed in animals has been attributed to the low intrinsic solubility. To enhance their GI absorption, we attempted to increase the solubility of these compounds with hydroxypropyl beta-cyclodextrin (HPB)4 and gamma-cyclodextrin (HPG). Compound I showed an increase in solubility over 1,000-fold with 25% HPB at 25 degrees C.