title: The discovery and structure-activity relationships of indole-based inhibitors of glutamate carboxypeptidase II.
abstract: A series of N-substituted 3-(2-mercaptoethyl)-1H-indole-2-carboxylic acids were synthesized as inhibitors of glutamate carboxypeptidase II (GCPII). Those containing carboxybenzyl or carboxyphenyl groups at the N-position exhibited potent inhibitory activity against GCPII. These indole-based compounds represent the first example of achiral GCPII inhibitors and demonstrate greater tolerance of the GCPII active site for ligands with significant structural difference from the endogenous substrate, N-acetyl-aspartylglutamate.
authors.affiliation: Eisai Research Institute, Baltimore, MD 21224, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Grella
authors.forename: Jessica
authors.initials: J
authors.lastname: Adams
authors.forename: James F
authors.initials: JF
authors.lastname: Berry
authors.forename: Greg
authors.initials: G
authors.lastname: Delahanty
authors.forename: Dana V
authors.initials: DV
authors.lastname: Ferraris
authors.forename: Pavel
authors.initials: P
authors.lastname: Majer
authors.forename: Chiyou
authors.initials: C
authors.lastname: Ni
authors.forename: Krupa
authors.initials: K
authors.lastname: Shukla
authors.forename: Scott A
authors.initials: SA
authors.lastname: Shuler
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
authors.forename: Marigo
authors.initials: M
authors.lastname: Stathis
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
mesh_terms: D002264:Carboxylic Acids; D004353:Drug Evaluation, Preclinical; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002264:Carboxylic Acids; D007211:Indoles; D011480:Protease Inhibitors; C058980:indole-2-carboxylic acid; D043425:Glutamate Carboxypeptidase II