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

Abstract

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.

Myelin repair in Alzheimer’s disease: a review of biological pathways and potential therapeutics

“…KARI201 normalizes ASM activity without affecting protein level of ASM or mRNA transcript level of SMPD1 , the gene coding for ASM. However, this drug is associated with significantly reduced Aβ levels and improved autophagic and phagocytic microglial activity [ 101 ]. ASM inhibition also encourages OL maturation and/or survival [ 102 ].…”

“…ASM inhibition also encourages OL maturation and/or survival [ 102 ]. KARI201 is also found to have a dual action as a ghrelin receptor agonist; agonism of this receptor is known to promote hippocampal synaptic density, plasticity, and neurogenesis in the context of AD [ 101 ].…”

Diverse Roles of Ceramide in the Progression and Pathogenesis of Alzheimer’s Disease

“…To date, different types of ASM inhibitors have been reported, including natural, non-natural, physiological, and functional inhibitors. Besides, several research groups have reported some direct inhibitors of ASM including KARI 201 [ 93 ], ARC39 [ 94 ], AD2765 [ 95 ], and SMA-7 [ 96 ]. In addition, α-mangostin [ 97 ], cowanol, and cowanin [ 85 ] are natural ASM inhibitors, while various physiological inhibitors, including L-αphosphatidyl-D-myoinositol-3,5-biphosphate [ 98 ] and phosphatidyl-myo-inositol-3,4,5-triphosphate [ 99 ] also inhibits ASM.…”

Acid sphingomyelinase inhibition improves motor behavioral deficits and neuronal loss in an amyotrophic lateral sclerosis mouse model

“…However, these inhibitors lack specificity, have off-target effects, and have unclear mechanisms of therapeutic action in neurodegenerative diseases. Based on this, a new small compound was recently identified as a selective and direct ASM inhibitor without off-target effects ( 31 ). This ASM inhibitor is significantly effective in improving neuroinflammation, autophagy dysfunction, synapse loss, neuronal survival, and activity in neurodegenerative diseases ( 31 ).…”

“…Based on this, a new small compound was recently identified as a selective and direct ASM inhibitor without off-target effects ( 31 ). This ASM inhibitor is significantly effective in improving neuroinflammation, autophagy dysfunction, synapse loss, neuronal survival, and activity in neurodegenerative diseases ( 31 ). Moreover, this inhibitor exhibits excellent bioavailability, central nervous system distribution, and microsomal stability.…”