KARI 201
KARI 201 is an orally active, blood-brain barrier-penetrant bifunctional small molecule. KARI 201 is a selective inhibitor of ASM and an agonist of GHSR-1a. KARI 201 competitively binds ASM, inhibits ASM activity to reduce intracellular ceramide levels, restores lysosomal biogenesis, and repairs impaired autophagic flux in neurons. KARI 201 activates GHSR-1a and induces calcium influx. KARI 201 ameliorates Alzheimer's disease-related pathology, age-related sarcopenia phenotypes, and postoperative ileus-related symptoms. KARI 201 can be used in Alzheimer's disease-related research.
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- No. CAS: 2376132-22-6
- Fòrmula: C14H28N4O2
- Peso molecular:284.40
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Almacenamiento:
Please store the product under the recommended conditions in the Certificate of Analysis.
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Actividad biológica
Descripciòn
IC50 & Target
[2]|
GHSR1a 3.36 μM (EC50) |
Cellular Effect
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Cell Line
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Type | Value | Description | References |
|---|---|---|---|---|
| HEK293-A | EC50 |
3.36 μM
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Agonism of human GHSR-1a in HEK293A cells assessed by intracellular calcium influx using Eurofins functional assay.
Agonism of human GHSR-1a in HEK293A cells assessed by intracellular calcium influx using Eurofins functional assay.
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41923173 |
In Vitro
KARI 201 prevents ASM-induced increases in LC3-II and p62, and enhances TFEB/Lamp1 expression, improving autophagic degradation in neurons[1].
KARI 201 restores neurosphere formation, proliferation, survival gene expression, and synaptic density in oligomeric Aβ42-exposed mouse hippocampal NSCs and mouse/human hippocampal neurons, and reduces ASM activity/ceramide[1].
KARI 201 is a competitive ASM inhibitor relative to sphingomyelin, increasing KM to 332.5, 433.9, and 572.6 μM in biochemical ASM assays; it is a selective ASM inhibitor with no significant off-target activity against 430 kinases and 38 other enzymes, and directly inhibits secreted ASM in PS1-derived conditioned medium[1].
KARI 201 inhibits ASM activity and ceramide production in PS1 familial AD fibroblasts without altering SMPD1 mRNA/ASM protein or the lysosomal compartment[1].
KARI 201 activates human GHSR-1a in HEK293A/GHSR-1a stable cells, inducing intracellular calcium influx with an EC50 of 3.36 μM[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
In Vivo
KARI 201 (1-10 mg/kg/day; p.o.; from 7.5 to 9 months of age) dose-dependently inhibits ASM activity and ameliorates amyloid pathology, neuroinflammation, autophagic dysfunction, synaptic loss, hippocampal neurogenesis, LTP, memory deficits, and AD-related transcriptomic alterations in APP/PS1 AD mice, with the strongest effects at 10 mg/kg[1].
KARI 201 (10 mg/kg; p.o.; daily; 28 days) increases circulating GH and preserves skeletal muscle mass and motor performance in aging-related sarcopenia C57BL/6 mice[2].
KARI 201 inhibits ASM activity and ameliorates AD-like neuropathology in 5 x FAD mice[1].
KARI 201 (10 mg/kg; p.o.; daily; 14 days) activates hypothalamic ARC neurons and increases food intake in C57BL/6 mice[2].
KARI 201 (10-30 mg/kg; p.o.; single administration) improves gastrointestinal transit and food intake in postoperative ileus C57BL/6 mice[2].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:APP/PS1 (transgenic AD model; 7.5-month-old at start, 9-month-old at analysis)[1]
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Dosage:1 mg/kg; 5 mg/kg; 10 mg/kg
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Administration:p.o.; daily; from 7.5 to 9 months of age
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Result:Suppressed ASM activity dose‑dependently and normalized ASM function at 10 mg/kg independent of Smpd1/ASM expression.
Mitigated Aβ‑tau pathologies, cognitive‑behavioral impairments and neuroinflammation without perturbing APP‑Bace‑1 signaling.
Lowered neuronal ASM‑ceramide while maintaining microglial sphingolipid homeostasis.
Restored autophagic‑lysosomal function and microglial Aβ phagocytosis.
Promoted hippocampal neurogenesis, CA1‑LTP and cerebral BDNF with no toxicity to survival and body weight.
Reversed disease‑relevant transcriptomic disturbances across ribosomal, G‑protein‑signaling and cognition‑associated gene modules.
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Animal Model:C57BL/6 (both male and female)[2]
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Dosage:10, 20 or 30 mg/kg
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Administration:p.o.; single administration
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Result:Gastric emptying improved.
Colonic transit time shortened.
Faecal pellet output increased.
Food intake increased.
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Animal Model:C57BL/6 (3 and 23 months old)[2]
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Dosage:10 mg/kg
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Administration:p.o.; daily; 28 days
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Result:Elevated plasma GH, augmented gastrocnemius mass and improved rota‑rod performance, with unchanged grip strength, body weight and fat mass.
Repressed MuRF1, boosted mTOR, and heightened AKT‑S6K‑S6 phosphorylation.
Down‑regulated muscle‑atrophy‑related genes and induced trending up‑regulation of myogenic genes.
Enlarged cross‑sectional area of Type IIA, IIB, IIX muscle fibres.
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Animal Model:BALB/c (8-week-old; both male and female)[2]
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Dosage:10 mg/kg; 30 mg/kg
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Administration:p.o.; daily; from Day 9 to Day 24
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Result:Improved food intake, preserves skeletal muscle mass and functional recovery in BALB/c mice with CT26 cancer cachexia without affecting tumour growth.
Chemical Information
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No. CAS 2376132-22-6
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Peso molecular 284.40
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Fòrmula C14H28N4O2
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SMILES
NC(CO)(CO)C(N=N1)=CN1CCCCCCCCC
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
KARI 201 Related Classifications
HY-171962 Related Classifications
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