Issue 1, 2013
From the journal:

MedChemComm

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

Jaclyn L. Henderson,a   Aarti Sawant-Basak,a   Jamison B. Tuttle,a   Amy B. Dounay,a   Laura A. McAllister,a   Jayvardhan Pandit,a   Suobao Rong,a   Xinjun Hou,a   Bruce M. Bechle,a   Ji-Young Kim,a   Vinod Parikh,a   Somraj Ghosh,a   Edelweiss Evrard,a   Laura E. Zawadzke,a   Michelle A. Salafia,a   Brian Rago,a   Ronald S. Obach,a   Alan Clark,a   Kari R. Fonseca,a   Cheng Changa  and  Patrick R. Verhoest*a  

* Corresponding authors

a Neuroscience Medicinal Chemistry, 700 Main Street, Cambridge, MA 12139, USA
E-mail: patrick.r.verhoest@pfizer.com

Abstract

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.

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

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Article information

DOI
https://doi.org/10.1039/C2MD20166F
Article type
Concise Article
Submitted
25 Jun 2012
Accepted
07 Aug 2012
First published
13 Aug 2012

Med. Chem. Commun., 2013,4, 125-129

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

J. L. Henderson, A. Sawant-Basak, J. B. Tuttle, A. B. Dounay, L. A. McAllister, J. Pandit, S. Rong, X. Hou, B. M. Bechle, J. Kim, V. Parikh, S. Ghosh, E. Evrard, L. E. Zawadzke, M. A. Salafia, B. Rago, R. S. Obach, A. Clark, K. R. Fonseca, C. Chang and P. R. Verhoest, Med. Chem. Commun., 2013, 4, 125 DOI: 10.1039/C2MD20166F

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