Nerve growth factor (NGF) signaling through tropomyosin receptor kinase A (TrkA) mediates the induction and modulation of pain associated with injury, inflammation, and chronic pain states. Activation of TrkA by NGF triggers downstream intracellular processes and protein expression that increase the sensitivity of nociceptors. Inhibition of the NGF/TrkA pathway as a novel approach for the treatment of pain has been clinically validated with NGF-neutralizing monoclonal antibodies. For example, tanezumab (Phase III) has demonstrated efficacy in chronic osteoarthritis and lower back pain. Our approach has focused on the identification of small molecules inhibitors of TrkA for the treatment of pain. We previously described a potent, selective, and orally bioavailable series of benzamides derived from a screening hit. Because of literature reports of CNS cholinergic deficits in rats following direct injection of anti-NGF antibodies in the brain, we sought peripherally selective molecules to mitigate the risk of cognitive dysfunction due to central TrkA inhibition. To achieve peripheral selectivity, we utilized P-glycoprotein (P-gp) susceptibility as a primary design feature. Using TrkA phosphorylation (pTrkA) as functional assay of target engagement, we demonstrated that these compounds exhibited lower plasma IC50 values for pTrkA in skin compared to brain. This presentation will describe the relationship between peripheral selectivity, as measured by the shift in IC50 values, and in vitro P-gp efflux ratio, and limitations discovered for this series of compounds. Also highlighted will be other approaches attempted to increase peripheral selectivity, including reducing permeability, and the subsequent impact on oral bioavailability. The evolution and profiles of representative leading molecules will be discussed. Lastly, the binding site and key interactions for this novel allosteric class of TrkA inhibitors will be illustrated using X-ray crystal structures.

Impact of P-gp susceptibility on brain penetration for a series of potent, selective, and orally bioavailable TrkA inhibitors

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.