ChemicalBook CAS DataBase List 2278265-85-1

2278265-85-1

Name	Acetamide, 2-(4-chlorophenoxy)-N-[3-[5-[cis-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl]bicyclo[1.1.1]pent-1-yl]-
CAS	2278265-85-1
Molecular Formula	C20H19ClF3N3O4
Molecular Weight	457.83
MOL File	2278265-85-1.mol

Chemical Properties

density	1.51±0.1 g/cm3(Predicted)
solubility	Acetonitrile: Slightly soluble: 0.1-1 mg/ml DMSO: Sparingly soluble: 1-10 mg/ml Ethanol: Sparingly soluble: 1-10 mg/ml
form	Solid
pka	13.43±0.40(Predicted)
color	White to light yellow

Hazard Information

Uses

DNL343 is a potent, selective, orally active and brain-penetrant activator of eukaryotic initiation factor eIF2B. DNL343 inhibits the activity of the integrated stress response (ISR) in the central nervous system (CNS) and reverses neurodegeneration and neuroinflammation. DNL343 also prevents motor dysfunction and premature death in eIF2B loss-of-function (LOF) mutant mice. DNL343 can be used in the study of neurodegenerative diseases[1][2][3].

in vivo

DNL343 (50 mg/kg; p.o.; once daily for 2 days) inhibits ISR activation in the brain of the Eif 2b5 R191H knock-in mouse model^[2]. DNL343 (0-12 mg/kg; i.g.; once daily for 2 or 14 days) inhibits the expression of ISR-dependent transcripts in ONC model mice in a dose-dependent manner^[3]. DNL343 (100 mg/kg; mixed in food for 4 weeks) restores normal weight gain in eIF2B LOF mice at the end stage of CNS ISR disease and reduces the elevated expression of ISR transcripts in the brain of eIF2B LOF^[3].

Animal Model:	Acute ISR-driven Neurodegenerative Disease Model of Optic Nerve Compression in Wild-type Mice^[3]
Dosage:	0、0.75、3 and 12 mg/kg
Administration:	i.g.; ONC is given once three hours after surgery and then once daily for two or fourteen days.
Result:	Reduced axonal degeneration at a dose of 12 mg/kg and significantly reduced retinal ganglion cell (RGC) loss at doses of 3 and 12 mg/kg.

Animal Model:	19-26 weeks old eIF2B LOF model mice^[3]
Dosage:	100 mg/kg
Administration:	The diet containing DNL343 at a concentration of 100 mg/kg was fed for 4 weeks
Result:	Blocked ISR activation and reversed ISR activation in mice with advanced disease.

References

[1] Yulyaningsih E, et al. DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response[J]. bioRxiv, 2023: 2023.8.21.554203
[2] Craig R A, et al. Discovery of DNL343: A Potent, Selective, and Brain-Penetrant eIF2B Activator Designed for the Treatment of Neurodegenerative Diseases[J]. Journal of Medicinal Chemistry, 2024, 67(7): 5758-5782. DOI:10.1021/acs.jmedchem.3c02422
[3] Yulyaningsih E, et al. DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response[J]. Elife, 2024, 12: RP92173. DOI:10.7554/eLife.92173

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