Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids

A series of aryl sulfonamides of 5,6-disubstituted anthranilic acids were identified as potent inhibitors of methionine aminopeptidase-2 (MetAP2). Small alkyl groups and 3-furyl were tolerated at the 5-position of anthranilic acid, while –OCH 3, CH 3, and Cl were found optimal for the 6-position. Pl...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters 2007-05, Vol.17 (10), p.2817-2822
Main Authors:	Wang, Gary T., Mantei, Robert A., Kawai, Megumi, Tedrow, Jason S., Barnes, David M., Wang, Jieyi, Zhang, Qian, Lou, Pingping, Garcia, Lora A., Bouska, Jennifer, Yates, Melinda, Park, Chang, Judge, Russell A., Lesniewski, Richard, Sheppard, George S., Bell, Randy L.
Format:	Article
Language:	eng
Subjects:	Aminopeptidases - antagonists & inhibitors Aminopeptidases - chemistry Antineoplastic agents Biological and medical sciences General aspects Lead - chemistry Medical sciences Metalloendopeptidases - antagonists & inhibitors Metalloendopeptidases - chemistry Methionine aminopeptidase-2 (MetAP2) inhibitors Models, Molecular Molecular Structure ortho-Aminobenzoates - chemistry ortho-Aminobenzoates - pharmacology Pharmacology. Drug treatments Protein Conformation Structure-Activity Relationship Sulfonamides - chemistry Sulfonamides of 5,6-disubstituted anthranilic acids
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Summary:	A series of aryl sulfonamides of 5,6-disubstituted anthranilic acids were identified as potent inhibitors of methionine aminopeptidase-2 (MetAP2). Small alkyl groups and 3-furyl were tolerated at the 5-position of anthranilic acid, while –OCH 3, CH 3, and Cl were found optimal for the 6-position. Placement of 2-aminoethoxy group at the 6-position enabled interaction with the second Mn 2+ but did not result in enhancement in potency. Introduction of a tertiary amino moiety at the ortho-position of the sulfonyl phenyl ring gave reduced protein binding and improved cellular activity, but led to lower oral bioavailability.
ISSN:	0960-894X 1464-3405