Discovery and evaluation of HW161023 as a potent and orally active AAK1 inhibitor

AAK1, also known as AP2-associated protein kinase 1, is an enzyme that belongs to the family of serine/threonine protein kinases. It regulates the assembly and disassembly of clathrin-coated pits and thereby protein endocytosis, by phosphorylating the μ2 subunit of the AP2 complex, which is a key component of clathrin-coated vesicles. LX9211 is currently the only selective small molecule AAK1 inhibitor at the clinical trial stage for diabetic peripheral neuropathic pain, which was found to be safe and well tolerated in healthy participants in phase I clinical trials. The present manuscript described a series of fused-ring derivatives as a novel class of potent AAK1 inhibitors, resulting in the discovery of compound 5, namely HW161023, which showed high inhibitory potency against AAK1 enzyme and satisfactory oral pharmacokinetic profile with weaker HepG2 cell toxicity and hERG inhibition than LX9211.