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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Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2007-05, Vol.17 (10), p.2817-2822 |
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Hauptverfasser: | , , , , , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0960-894X 1464-3405 |
DOI: | 10.1016/j.bmcl.2007.02.062 |