title: Lead optimization of methionine aminopeptidase-2 (MetAP2) inhibitors containing sulfonamides of 5,6-disubstituted anthranilic acids.
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.
authors.affiliation: Cancer Research, Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gary.t.wang@abbott.com
authors.forename: Gary T
authors.initials: GT
authors.lastname: Wang
authors.forename: Robert A
authors.initials: RA
authors.lastname: Mantei
authors.forename: Megumi
authors.initials: M
authors.lastname: Kawai
authors.forename: Jason S
authors.initials: JS
authors.lastname: Tedrow
authors.forename: David M
authors.initials: DM
authors.lastname: Barnes
authors.forename: Jieyi
authors.initials: J
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.forename: Pingping
authors.initials: P
authors.lastname: Lou
authors.forename: Lora A
authors.initials: LA
authors.lastname: Garcia
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bouska
authors.forename: Melinda
authors.initials: M
authors.lastname: Yates
authors.forename: Chang
authors.initials: C
authors.lastname: Park
authors.forename: Russell A
authors.initials: RA
authors.lastname: Judge
authors.forename: Richard
authors.initials: R
authors.lastname: Lesniewski
authors.forename: George S
authors.initials: GS
authors.lastname: Sheppard
authors.forename: Randy L
authors.initials: RL
authors.lastname: Bell
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D007854:Lead / Q000737:chemistry*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D013449:Sulfonamides; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007854:Lead; D000626:Aminopeptidases; C106541:methionine aminopeptidase 2; D008666:Metalloendopeptidases