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Papers of the Week

Papers: 24 Jun 2023 - 30 Jun 2023

Basic Science

Animal Studies, In Vitro Studies, Neurobiology, Pharmacology/Drug Development


2023 Jun 03

Med Chem Res


Discovery of pyrrolo[2,1-][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.


Dzierba CD, Dasgupta B, Karageorge G, Kostich W, Hamman B, Allen J, Esposito KM, Padmanabha R, Grace J, Lentz K, Morrison J, Morgan D, Easton A, Bourin C, Browning MR, Rajamani R, Good A, Parker DD, Muckelbauer JK, Khan J, Camac D, Ghosh K, Halan V, Lippy JS, Santone KS, Denton RR, Westphal R, Bristow LJ, Conway CM, Bronson JJ, Macor JE


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. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.