Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I

Fady N Akladios; Naveed A Nadvi; Joohong Park; Jane R Hanrahan; Vimal Kapoor; Mark D Gorrell; W Bret Church

doi:10.1016/j.bmcl.2011.12.138

Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I

Bioorg Med Chem Lett. 2012 Feb 15;22(4):1579-81. doi: 10.1016/j.bmcl.2011.12.138. Epub 2012 Jan 10.

Authors

Fady N Akladios¹, Naveed A Nadvi, Joohong Park, Jane R Hanrahan, Vimal Kapoor, Mark D Gorrell, W Bret Church

Affiliation

¹ Faculty of Pharmacy A15, The University of Sydney, Sydney, NSW 2006, Australia.

PMID: 22281190
DOI: 10.1016/j.bmcl.2011.12.138

Abstract

Herein we report 6-ethoxy-6-oxo-5-(2-phenylhydrazono) hexanoic acid and 3-(2-carboxyethyl)-1H-indole-2-carboxylic acid derivatives as synthetically accessible leads for human kynurenine aminotransferase-I (KAT-I) inhibitors. In total, 12 compounds were synthesized and their biological activities were determined using the HPLC-UV based KAT-I inhibition assay. Of the 12 compounds synthesized, 10 were found to inhibit human KAT-I and the most active compound was found to be 5-(2-(4-chlorophenyl) hydrazono)-6-ethoxy-6-oxohexanoic acid (9a) with an IC(50) of 19.8 μM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Caproates / chemical synthesis*
Caproates / chemistry
Caproates / pharmacology
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Humans
Hydrazines / chemical synthesis*
Hydrazines / chemistry
Hydrazines / pharmacology
Inhibitory Concentration 50
Models, Molecular*
Molecular Structure
Schizophrenia / drug therapy
Transaminases / antagonists & inhibitors*

Substances

5-(2-(4-chlorophenyl)hydrazono)-6-ethoxy-6-oxohexanoic acid
Caproates
Enzyme Inhibitors
Hydrazines
Transaminases
kynurenine-oxoglutarate transaminase