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

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• 作者：Gary T. Wang ; Robert A. Mantei ; Megumi Kawai ; Jason S. Tedrow ; David M. Barnes ; Jieyi Wang ; Qian Zhang ; Pingping Lou ; Lora A. Garcia ; Jennifer Bouska ; et al.
• 关键词：Methionine aminopeptidase-2 (MetAP2) inhibitors ; Sulfonamides of 5 ; 6-disubstituted anthranilic acids
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2007
• 出版时间：15 May 2007
• 年：2007
• 卷：17
• 期：10
• 页码：2817-2822
• 全文大小：366 K

文摘

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 –OCH₃, CH₃, and Cl were found optimal for the 6-position. Placement of 2-aminoethoxy group at the 6-position enabled interaction with the second Mn²⁺ 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.