Discovery of hydroxamate bioisosteres as KAT II inhibitors with improved oral bioavailability and pharmacokinetics

A series of kynurenine aminotransferase II (KAT II) inhibitors has been developed replacing the hydroxamate motif with a bioisostere. Triazolinones or triazoles have proven to be effective replacements with significantly improved pharmacokinetics including reduced clearance and increased bioavailabi...

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Published in:MedChemComm 2013, Vol.4 (1), p.125-129
Main Authors: Henderson, Jaclyn L., Sawant-Basak, Aarti, Tuttle, Jamison B., Dounay, Amy B., McAllister, Laura A., Pandit, Jayvardhan, Rong, Suobao, Hou, Xinjun, Bechle, Bruce M., Kim, Ji-Young, Parikh, Vinod, Ghosh, Somraj, Evrard, Edelweiss, Zawadzke, Laura E., Salafia, Michelle A., Rago, Brian, Obach, Ronald S., Clark, Alan, Fonseca, Kari R., Chang, Cheng, Verhoest, Patrick R.
Format: Article
Language:English
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Summary:A series of kynurenine aminotransferase II (KAT II) inhibitors has been developed replacing the hydroxamate motif with a bioisostere. Triazolinones or triazoles have proven to be effective replacements with significantly improved pharmacokinetics including reduced clearance and increased bioavailability. An X-ray crystal structure of an inhibitor bound in KAT II confirms that the irreversible binding to the co-factor is maintained and that the heterocycles make productive hydrogen bonds to the arginine-399.
ISSN:2040-2503
2040-2511
DOI:10.1039/C2MD20166F