Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions

A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure–activity relationships (SAR) in conjunctio...

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Published inACS medicinal chemistry letters Vol. 4; no. 1; pp. 37 - 40
Main Authors Tuttle, Jamison B, Anderson, Marie, Bechle, Bruce M, Campbell, Brian M, Chang, Cheng, Dounay, Amy B, Evrard, Edelweiss, Fonseca, Kari R, Gan, Xinmin, Ghosh, Somraj, Horner, Weldon, James, Larry C, Kim, Ji-Young, McAllister, Laura A, Pandit, Jayvardhan, Parikh, Vinod D, Rago, Brian J, Salafia, Michelle A, Strick, Christine A, Zawadzke, Laura E, Verhoest, Patrick R
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 10.01.2013
Subjects
Letter
dose response modeling
irreversible inhibition
kynurenine amino transferase
hydroxamic acid
schizophrenia
kynurenic acid
in vivo microdialysis
aryl hydrocarbon receptor
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Abstract A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure–activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.
AbstractList A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure–activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4 , a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact / K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.
A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a role in schizophrenia and other psychiatric and neurological disorders. The utilization of structure–activity relationships (SAR) in conjunction with X-ray crystallography led to the discovery of hydroxamate 4, a disubstituted analogue that has a significant potency enhancement due to a novel interaction with KAT II. The use of k inact/K i to assess potency was critical for understanding the SAR in this series and for identifying compounds with improved pharmacodynamic profiles.
Author Rago, Brian J
Pandit, Jayvardhan
Ghosh, Somraj
McAllister, Laura A
Zawadzke, Laura E
Dounay, Amy B
Strick, Christine A
Evrard, Edelweiss
James, Larry C
Salafia, Michelle A
Tuttle, Jamison B
Bechle, Bruce M
Gan, Xinmin
Parikh, Vinod D
Verhoest, Patrick R
Chang, Cheng
Anderson, Marie
Kim, Ji-Young
Campbell, Brian M
Fonseca, Kari R
Horner, Weldon
AuthorAffiliation Pfizer Worldwide Research and Development
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Keywords dose response modeling
irreversible inhibition
kynurenine amino transferase
hydroxamic acid
schizophrenia
kynurenic acid
in vivo microdialysis
aryl hydrocarbon receptor
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Snippet A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a...
A series of aryl hydroxamates recently have been disclosed as irreversible inhibitors of kynurenine amino transferase II (KAT II), an enzyme that may play a...
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Title Structure-Based Design of Irreversible Human KAT II Inhibitors: Discovery of New Potency-Enhancing Interactions
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