Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class ofHighly Selective, CNS-Penetrable, and Orally Active AdaptorProtein-2-Associated Kinase 1 (AAK1) Inhibitors for the PotentialTreatment of Neuropathic Pain

Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treatingneuropathic pain. BMS-986176/LX-9211 (4), as a highly selective, CNS-penetrable, and potent AAK1 inhibitor, has advanced intophase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, severaladditional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these,compounds43and58showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinalcord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties.Compound58, a central pyridine isomer of BMS-986176/LX-9211 (4), was 4-fold more potent than4in vitro and showed lowerplasma exposure needed to achieve similar efficacy compared to4in the CCI rat model. However, both43and58showed aninferior preclinical toxicity profile compared to4