Tropomysin receptor kinases (Trks) are a family of cell surface receptor kinases including TrkA, TrkB and TrkC, that play an important role in cell signaling. When a neurotrophic partner binds with the extracellular domain of each of these kinases, activation of the receptor occurs. Activation of TrkA by nerve growth factor (NGF) results in an increase in sensitivity of nociceptors leading to chronic sensitization and pain. Direct inhibition of TrkA kinase is one possible approach to inhibit NGF/TrkA signaling. While inhibition of the NGF/TrkA pathway has been clinically validated with NGF-neutralizing monocloidal antibodies (tanezumab, Phase III), our interest was in small molecule inhibitors. From HTS screening, two small molecule pan-Trk inhibitor leads were discovered that bind to the TrkA enzyme in the DFG-out mode, spanning both the kinase active site and the nearby allosteric pocket. Optimization of these lead compounds was explored. Azaindazole hinge binders improved potency 10-30-fold in an open urea series, with selective modulation of P-gp susceptibility possible. Gem-dimethyl cyclic urea analogs improved potency 280-fold by water expulsion, while the combination results in cell-active analogs with moderate plasma clearance in rat.

Urea TrkA kinase inhibitors: How the hinge helped open the door to improved potency

254th National Meeting (2017)

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