title: GluK1 antagonists from 6-(tetrazolyl)phenyl decahydroisoquinoline derivatives: in vitro profile and in vivo analgesic efficacy.
abstract: We have explored the decahydroisoquinoline scaffold, bearing a phenyl tetrazole, as GluK1 antagonists with potential as oral analgesics. We have established the optimal linker atom between decahydroisoquinoline and phenyl rings and demonstrated an improvement of both the affinity for the GluK1 receptor and the selectivity against the related GluA2 receptor with proper phenyl substitution. In this Letter, we also disclose in vivo data that led to the discovery of LY545694·HCl, a compound with oral efficacy in two persistent pain models.
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: David K
authors.initials: DK
authors.lastname: Clawson
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; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D010146:Pain / Q000188:drug therapy*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007546:Isoquinolines; D011355:Prodrugs; D018092:Kainic Acid Receptors; D013777:Tetrazoles; C000593718:dasolampanel etibutil
keywords: Acid isoster; Decahydroisoquinolines; GluK1 antagonists; Pain; Prodrug