Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer's disease mice

Min Hee Park, Kang Ho Park, Byung Jo Choi, Wan Hui Han, Hee Ji Yoon, Hye Yoon Jung, Jihoon Lee, Im Sook Song, Dong Yu Lim, Min Koo Choi, Yang Ha Lee, Cheol Min Park, Ming Wang, Jihoon Jo, Hee Jin Kim, Seung Hyun Kim, Edward H. Schuchman, Hee Kyung Jin, Jae Sung Bae

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Alzheimer's disease (AD) is characterized by complex, multifactorial neuropathology, suggesting that small molecules targeting multiple neuropathological factors are likely required to successfully impact clinical progression. Acid sphingomyelinase (ASM) activation has been recognized as an important contributor to these neuropathological features in AD, leading to the concept of using ASM inhibitors for the treatment of this disorder. Here we report the identification of KARI 201, a direct ASM inhibitor evaluated for AD treatment. KARI 201 exhibits highly selective inhibition effects on ASM, with excellent pharmacokinetic properties, especially with regard to brain distribution. Unexpectedly, we found another role of KARI 201 as a ghrelin receptor agonist, which also has therapeutic potential for AD treatment. This dual role of KARI 201 in neurons efficiently rescued neuropathological features in AD mice, including amyloid beta deposition, autophagy dysfunction, neuroinflammation, synaptic loss, and decreased hippocampal neurogenesis and synaptic plasticity, leading to an improvement in memory function. Our data highlight the possibility of potential clinical application of KARI 201 as an innovative and multifaceted drug for AD treatment.

Original languageEnglish
Article numbere2115082119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
StatePublished - 18 Jan 2022


  • ASM direct inhibitor
  • Alzheimer's disease
  • GHSR1 alpha agonist
  • Memory improvement
  • Small compound


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