Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic Pain

Recent mouse knockout studies identified
adapter protein-2-associated
kinase 1 (AAK1) as a viable target for treating neuropathic pain.
BMS-986176/LX-9211 (4), as a highly selective, CNS-penetrable,
and potent AAK1 inhibitor, has advanced into phase II human trials.
On exploring the structure–activity relationship (SAR) around
this biaryl alkyl ether chemotype, several additional compounds were
found to be highly selective and potent AAK1 inhibitors with good
druglike properties. Among these, compounds 43 and 58 showed very good efficacy in two neuropathic pain rat models
and had excellent CNS penetration and spinal cord target engagement.
Both compounds also exhibited favorable physicochemical and oral pharmacokinetic
(PK) properties. Compound 58, a central pyridine isomer
of BMS-986176/LX-9211 (4), was 4-fold more potent than 4 in vitro and showed lower plasma exposure needed to achieve
similar efficacy compared to 4 in the CCI rat model.
However, both 43 and 58 showed an inferior
preclinical toxicity profile compared to 4.