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

被引：22

作者：

Tuttle, Jamison B. ^{[1
]}

Anderson, Marie ^{[1
]}

Bechle, Bruce M. ^{[1
]}

Campbell, Brian M. ^{[1
]}

Chang, Cheng ^{[1
]}

Dounay, Amy B. ^{[1
]}

Evrard, Edelweiss ^{[1
]}

Fonseca, Kari R. ^{[1
]}

Gan, Xinmin ^{[1
]}

Ghosh, Somraj ^{[1
]}

Horner, Weldon ^{[1
]}

James, Larry C. ^{[1
]}

Kim, Ji-Young ^{[1
]}

McAllister, Laura A. ^{[1
]}

Pandit, Jayvardhan ^{[1
]}

Parikh, Vinod D. ^{[1
]}

Rago, Brian J. ^{[1
]}

Salafia, Michelle A. ^{[1
]}

Strick, Christine A. ^{[1
]}

Zawadzke, Laura E. ^{[1
]}

Verhoest, Patrick R. ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Neurosci Med Chem, Groton, CT 06340 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 01期

关键词：

kynurenine amino transferase; kynurenic acid; aryl hydrocarbon receptor; irreversible inhibition; hydroxamic acid; dose response modeling; in vivo microdialysis; schizophrenia; CATION-PI INTERACTIONS; KYNURENIC ACID; CEREBROSPINAL-FLUID; ELEVATED LEVELS; SCHIZOPHRENIA; RECEPTOR; SITE;

D O I：

10.1021/ml300237v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：37 / 40

页数：4

共 20 条

[11] Structure-guided inhibitor design for human FAAH by interspecies active site conversion [J].

Mileni, Mauro ;

Johnson, Douglas S. ;

Wang, Zhigang ;

Everdeen, Daniel S. ;

Liimatta, Marya ;

Pabst, Brandon ;

Bhattacharya, Keshab ;

Nugent, Richard A. ;

Kamtekar, Satwik ;

Cravatt, Benjamin F. ;

Ahn, Kay ;

Stevens, Raymond C. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (35) :12820-12824

[12] Kynurenic acid: a metabolite with multiple actions and multiple targets in brain and periphery [J].

Moroni, Flavio ;

Cozzi, Andrea ;

Sili, Maria ;

Mannaioni, Guido .

JOURNAL OF NEURAL TRANSMISSION, 2012, 119 (02) :133-139

[13] Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia [J].

Nilsson, LK ;

Linderholm, KR ;

Engberg, G ;

Paulson, L ;

Blennow, K ;

Lindström, LH ;

Nordin, C ;

Karanti, A ;

Persson, P ;

Erhardt, S .

SCHIZOPHRENIA RESEARCH, 2005, 80 (2-3) :315-322

[14] Elevated levels of kynurenic acid in the cerebrospinal fluid of patients with bipolar disorder [J].

Olsson, Sara K. ;

Samuelsson, Martin ;

Saetre, Peter ;

Lindstrom, Leif ;

Jonsson, Erik G. ;

Nordin, Conny ;

Engberg, Goran ;

Erhardt, Sophie ;

Landen, Mikael .

JOURNAL OF PSYCHIATRY & NEUROSCIENCE, 2010, 35 (03) :195-199

[15]

Parsons CG, 1997, J PHARMACOL EXP THER, V283, P1264

[16] Modulators of the kynurenine pathway of tryptophan metabolism:: Synthesis and preliminary biological evaluation of (S)-4-(ethylsulfonyl)benzoylaianine, a potent and selective kynurenine aminotransferase II (KAT II) inhibitor [J].

Pellicciari, Roberto ;

Rizzo, Rosa C. ;

Costantino, Gabriele ;

Marinozzi, Maura ;

Amori, Laura ;

Guidetti, Paolo ;

Wu, Hui-Qiu ;

Schwarcz, Robert .

CHEMMEDCHEM, 2006, 1 (05) :528-+

[17] Reduction of Endogenous Kynurenic Acid Formation Enhances Extracellular Glutamate, Hippocampal Plasticity, and Cognitive Behavior [J].

Potter, Michelle C. ;

Elmer, Greg I. ;

Bergeron, Richard ;

Albuquerque, Edson X. ;

Guidetti, Paolo ;

Wu, Hui-Qiu ;

Schwarcz, Robert .

NEUROPSYCHOPHARMACOLOGY, 2010, 35 (08) :1734-1742

[18] CHARACTERIZATION OF HUMAN BRAIN KYNURENINE AMINOTRANSFERASES USING [H-3] KYNURENINE AS A SUBSTRATE [J].

SCHMIDT, W ;

GUIDETTI, P ;

OKUNO, E ;

SCHWARCZ, R .

NEUROSCIENCE, 1993, 55 (01) :177-184

[19] Increased cortical kynurenate content in schizophrenia [J].

Schwarcz, R ;

Rassoulpour, A ;

Wu, HQ ;

Medoff, D ;

Tamminga, CA ;

Roberts, RC .

BIOLOGICAL PSYCHIATRY, 2001, 50 (07) :521-530

[20]

Schwarcz R., Preparation of amino-piperazinylquinolonecarboxylates as kynurenine-amino-transferase in-hibitors, Patent No. [WO2009064836, 2009064836]

← 1 2 →