Identification and Characterization of a Blood-Brain Barrier Penetrant Inositol Hexakisphosphate Kinase (IP6K) Inhibitor

被引：0

作者：

Heitmann, Tyler ^{[1
]}

Liao, Gangling ^{[2
]}

Ernst, Glen ^{[2
]}

Poslusney, Michael ^{[2
]}

van Kralingen, Thomas ^{[2
]}

Li, Ye ^{[2
]}

Masi, Megan ^{[1
,4
]}

Depasquale, Michael ^{[2
]}

Buchler, Ingrid ^{[2
]}

Wei, Huijun ^{[1
,2
]}

Carr, Gregory V. ^{[1
,2
]}

Shlevkov, Evgeny ^{[2
]}

Lu, Mengsi ^{[3
]}

Jessen, Henning ^{[3
,4
]}

Barrow, James C. ^{[1
,2
]}

机构：

[1] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[2] Lieber Inst Brain Dev, Baltimore, MD 21205 USA

[3] Albert Ludwigs Univ, Inst Organ Chem, D-79104 Freiburg, Germany

[4] Albert Ludwigs Univ, CIBSS Ctr Integrat Biol Signaling Studies, D-79104 Freiburg, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 16期

关键词：

CELL-DEATH; GENE DELETION; PYROPHOSPHATES; PHOSPHORYLATION; PHOSPHATES; MIGRATION; INTERACTS; PATHWAY; GROWTH;

D O I：

10.1021/acs.jmedchem.4c00190

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inositol hexakisphosphate kinases (IP6Ks) have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to the pyrophosphate, 5-diphosphoinositol-1,2,3,4,6-pentakisphosphate (5-IP7). Most of the currently known potent IP6K inhibitors contain a critical carboxylic acid which limits blood-brain barrier (BBB) penetration. In this work, the synthesis and testing of a variety of carboxylic acid isosteres resulted in several new compounds with improved BBB penetration. The most promising compound has an IP6K1 IC50 of 16 nM with an improved brain/plasma ratio and a favorable pharmacokinetic profile. This series of brain penetrant compounds may be used to investigate the role of IP6Ks in CNS disorders.

引用

页码：13639 / 13665

页数：27

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