Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2‑Associated Kinase 1 Inhibitors

Adaptor 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 7 is a brain-penetrant, AAK1 inhibitor
that showed efficacy in animal models for neuropathic pain. One approach
we took to improve upon the potency of 7 involved tying
the amide back into the neighboring phenyl ring to form a bicyclic
heterocycle. Investigation of the structure–activity relationships
(SARs) of substituents on the resultant quinazoline and quinoline
ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved
enzyme and cellular potency compared to 7. The synthesis,
SAR, and in vivo evaluation of a series of quinazoline and quinoline-based
AAK1 inhibitors are described herein.