2. Academic Validation
  3. Identification and Characterization of a Blood-Brain Barrier Penetrant Inositol Hexakisphosphate Kinase (IP6K) Inhibitor

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

  • J Med Chem. 2024 Aug 22;67(16):13639-13665. doi: 10.1021/acs.jmedchem.4c00190.
Tyler Heitmann 1,  Gangling Liao 2,  Glen Ernst 2,  Michael Poslusney 2,  Thomas van Kralingen 2,  Ye Li 2,  Megan Masi 1,  Michael DePasquale 2,  Ingrid Buchler 2,  Huijun Wei 1 2,  Gregory V Carr 1 2,  Evgeny Shlevkov 2,  Mengsi Lu 3,  Henning Jessen 3,  James C Barrow 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, United States.
  • 2 Lieber Institute for Brain Development, 855 N. Wolfe Street, Baltimore, Maryland 21205, United States.
  • 3 Institute of Organic Chemistry and CIBSS─Centre for Integrative Biological Signaling Studies, Albert-Ludwigs-University, Albertstr. 21, Freiburg 79104, Germany.
PMID: 39096294 DOI: 10.1021/acs.jmedchem.4c00190
Abstract

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.

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