Discovery, Structure–Activity
Relationships,
and In Vivo Evaluation of Novel Aryl Amides as Brain Penetrant Adaptor
Protein 2‑Associated Kinase 1 (AAK1) Inhibitors for the Treatment
of Neuropathic Pain
posted on 2021-07-16, 20:14authored byRichard A Hartz, Vijay T. Ahuja, Susheel J. Nara, C.M. Vijaya Kumar, Jeffrey M. Brown, Linda J. Bristow, Ramkumar Rajamani, Jodi K. Muckelbauer, Daniel Camac, Susan E. Kiefer, Lisa Hunihan, Michael Gulianello, Martin Lewis, Amy Easton, Jonathan S. Lippy, Neha Surti, Sreenivasulu N. Pattipati, Manoj Dokania, Saravanan Elavazhagan, Kumaran Dandapani, Brian D. Hamman, Jason Allen, Walter Kostich, Joanne J. Bronson, John E. Macor, Carolyn D. Dzierba
Effective treatment of chronic pain,
in particular neuropathic
pain, without the side effects that often accompany currently available
treatment options is an area of significant unmet medical need. A
phenotypic screen of mouse gene knockouts led to the discovery that
adaptor protein 2-associated kinase 1 (AAK1) is a potential therapeutic
target for neuropathic pain. The synthesis and optimization of structure–activity
relationships of a series of aryl amide-based AAK1 inhibitors led
to the identification of 59, a brain penetrant, AAK1-selective
inhibitor that proved to be a valuable tool compound. Compound 59 was evaluated in mice for the inhibition of μ2 phosphorylation.
Studies conducted with 59 in pain models demonstrated
that this compound was efficacious in the phase II formalin model
for persistent pain and the chronic-constriction-injury-induced model
for neuropathic pain in rats. These results suggest that AAK1 inhibition
is a promising approach for the treatment of neuropathic pain.