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Brain Targeting of Acyl-CoA:Cholesterol

Brain Targeting of Acyl-CoA:Cholesterol

Kimiyuki Shibuya, Shigeru Morikawa, Masayoshi Miyamoto, Shin-Ichiro Ogawa, Yoshihiko Tsunenari, Yasuomi Urano, Noriko Noguchi

ACS Omega. 2019 Oct 2;4(16):16943-16955.

PMID: 31646241

Abstract:

An acyl-CoA:cholesterol O-acyltransferase-1 (ACAT-1/SOAT-1) inhibitor, K-604 is a promising drug candidate for the treatment of Alzheimer's disease and glioblastoma; however, it exhibits poor solubility in neutral water and low permeability across the blood-brain barrier. In this study, we report the successful delivery of K-604 to the brain via the intranasal route in mice using a hydroxycarboxylic acid solution. In cerebral tissue, the AUC of K-604 after intranasal administration (10 μL; 108 μg of K-604/mouse) was 772 ng·min/g, whereas that after oral administration (166 μg of K-604/mouse) was 8.9 ng·min/g. Thus, the index of brain-targeting efficiency was 133-fold based on the dose conversion. Even with intranasal administration of K-604 once per day for 7 days, the level of cholesteryl esters markedly decreased from 0.70 to 0.04 μmol/g in the mouse brain. Thus, this application will be a crucial therapeutic solution for ACAT-1 overexpressing diseases in the brain.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP217094321	K-604		217094-32-1	Price

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