title: GluK1 antagonists from 6-(carboxy)phenyl decahydroisoquinoline derivatives. SAR and evaluation of a prodrug strategy for oral efficacy in pain models.
abstract: The synthesis and structure-activity relationship of decahydroisoquinoline derivatives with various benzoic acid substitutions as GluK1 antagonists are described. Potent and selective antagonists were selected for a tailored prodrug approach in order to facilitate the evaluation of the new compounds in pain models after oral administration. Several diester prodrugs allowed for acceptable amino acid exposure and moderate efficacy in vivo.
authors.affiliation: Centro de Investigación Lilly, Avda. de la Industria, 30, 28108-Alcobendas, Madrid, Spain. Electronic address: Martinez-Perez_Jose_A@Lilly.com.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Perez
authors.forename: Smriti
authors.initials: S
authors.lastname: Iyengar
authors.forename: Harlan E
authors.initials: HE
authors.lastname: Shannon
authors.forename: David
authors.initials: D
authors.lastname: Bleakman
authors.forename: Andrew
authors.initials: A
authors.lastname: Alt
authors.forename: Brian M
authors.initials: BM
authors.lastname: Arnold
authors.forename: Michael G
authors.initials: MG
authors.lastname: Bell
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bleisch
authors.forename: Ana M
authors.initials: AM
authors.lastname: Castaño
authors.forename: Miriam
authors.initials: M
authors.lastname: Del Prado
authors.forename: Esteban
authors.initials: E
authors.lastname: Dominguez
authors.forename: Ana M
authors.initials: AM
authors.lastname: Escribano
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Filla
authors.forename: Ken H
authors.initials: KH
authors.lastname: Ho
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hudziak
authors.forename: Carrie K
authors.initials: CK
authors.lastname: Jones
authors.forename: Ana
authors.initials: A
authors.lastname: Mateo
authors.forename: Brian M
authors.initials: BM
authors.lastname: Mathes
authors.forename: Edward L
authors.initials: EL
authors.lastname: Mattiuz
authors.forename: Ann Marie L
authors.initials: AM
authors.lastname: Ogden
authors.forename: Rosa Maria A
authors.initials: RM
authors.lastname: Simmons
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Stack
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stratford
authors.forename: Mark A
authors.initials: MA
authors.lastname: Winter
authors.forename: Zhipei
authors.initials: Z
authors.lastname: Wu
authors.forename: Paul L
authors.initials: PL
authors.lastname: Ornstein
mesh_terms: D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D000882:Haplorhini; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010146:Pain / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D011355:Prodrugs; D018092:Kainic Acid Receptors
keywords: Decahydroisoquinolines; GluA2; GluK1 antagonists; Pain; Prodrug