Publications by authors named "J S Lippy"
Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1-][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1.
View Article and Find Full Text PDFArticle Synopsis
- Recent studies on mice suggest that AAK1 could be a promising target for treating neuropathic pain, which led to the development of a new drug called BMS-986176/LX-9211 that is currently in phase II trials.
- Researchers also discovered additional highly selective and effective AAK1 inhibitors through structure-activity relationship studies, which showed promising results in neuropathic pain models with strong ability to penetrate the CNS.
- Among these compounds, one central pyridine isomer proved to be four times more potent than BMS-986176/LX-9211 with better efficacy but had a less favorable toxicity profile in preclinical tests.
Recent mouse knockout studies identified adapter protein-2 associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. Potent small-molecule inhibitors of AAK1 have been identified and show efficacy in various rodent pain models. ()-1-((2',6-Bis(difluoromethyl)-[2,4'-bipyridin]-5-yl)oxy)-2,4-dimethylpentan-2-amine (BMS-986176/LX-9211) () was identified as a highly selective, CNS penetrant, potent AAK1 inhibitor from a novel class of bi(hetero)aryl ethers.
View Article and Find Full Text PDFAdaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain.
View Article and Find Full Text PDFArticle Synopsis
- * Research identified adaptor protein 2-associated kinase 1 (AAK1) as a potential target for neuropathic pain after screening mouse gene knockouts.
- * A selective AAK1 inhibitor was developed, which showed effectiveness in pain relief during tests on mice and rats, indicating that targeting AAK1 could be a viable strategy for treating neuropathic pain.