1201173-75-2Relevant academic research and scientific papers
Discovery of a Novel and Brain-Penetrant O-GlcNAcase Inhibitor via Virtual Screening, Structure-Based Analysis, and Rational Lead Optimization
Tawada, Michiko,Fushimi, Makoto,Masuda, Kei,Sun, Huikai,Uchiyama, Noriko,Kosugi, Yohei,Lane, Weston,Tjhen, Richard,Endo, Satoshi,Koike, Tatsuki
, p. 1103 - 1115 (2021)
O-GlcNAcase (OGA) has received increasing attention as an attractive therapeutic target for tau-mediated neurodegenerative disorders; however, its role in these pathologies remains unclear. Therefore, potent chemical tools with favorable pharmacokinetic profiles are desirable to characterize this enzyme. Herein, we report the discovery of a potent and novel OGA inhibitor, compound 5i, comprising an aminopyrimidine scaffold, identified by virtual screening based on multiple methodologies combining structure-based and ligand-based approaches, followed by sequential optimization with a focus on ligand lipophilicity efficiency. This compound was observed to increase the level of O-GlcNAcylated protein in cells and display suitable pharmacokinetic properties and brain permeability. Crystallographic analysis revealed that the chemical series bind to OGA via characteristic hydrophobic interactions, which resulted in a high affinity for OGA with moderate lipophilicity. Compound 5i could serve as a useful chemical probe to help establish a proof-of-concept of OGA inhibition as a therapeutic target for the treatment of tauopathies.
DIAMINO-PYRIDINE, PYRIMIDINE, AND PYRIDAZINE MODULATORS OF THE HISTAMINE H4 RECEPTOR
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Page/Page column 112-113, (2010/01/07)
Diamino-pyridine, pyrimidine and pyridazine compounds which may be used as H4 receptor modulators, and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by H4 receptor activity, such as allergy, asthma, autoimmune diseases, and pruritis.
