Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids |
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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 |
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Affiliation: | Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gary.t.wang@abbott.com |
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Abstract: | 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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