title: Discovery of tetrahydroisoquinoline-based CXCR4 antagonists.
abstract: A de novo hit-to-lead effort involving the redesign of benzimidazole-containing antagonists of the CXCR4 receptor resulted in the discovery of a novel series of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogues. In general, this series of compounds show good potencies (3-650 nM) in assays involving CXCR4 function, including both inhibition of attachment of X4 HIV-1IIIB virus in MAGI-CCR5/CXCR4 cells and inhibition of calcium release in Chem-1 cells. Series profiling permitted the identification of TIQ-(R)-stereoisomer 15 as a potent and selective CXCR4 antagonist lead candidate with a promising in vitro profile. The drug-like properties of 15 were determined in ADME in vitro studies, revealing low metabolic liability potential. Further in vivo evaluations included pharmacokinetic experiments in rats and mice, where 15 was shown to have oral bioavailability (F = 63%) and resulted in the mobilization of white blood cells (WBCs) in a dose-dependent manner.
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Valarie M
authors.initials: VM
authors.lastname: Truax
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Brooke M
authors.initials: BM
authors.lastname: Katzman
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Prosser
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Ana A
authors.initials: AA
authors.lastname: Alcaraz
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Manohar T
authors.initials: MT
authors.lastname: Saindane
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Randy B
authors.initials: RB
authors.lastname: Howard
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Deborah
authors.initials: D
authors.lastname: Culver
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Arrendale
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Prahbakar R
authors.initials: PR
authors.lastname: Gruddanti
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Evers
authors.affiliation: Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Natchus
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States ; Emory Institute for Drug Development, 954 Gatewood Road NE, Atlanta, Georgia 30329, United States.
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.affiliation: Department of Chemistry, Emory University , 1515 Dickey Drive, Atlanta, Georgia 30322, United States.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Wilson
keywords: CXCR4 antagonists; CXCR4 receptor; HIV; Tetrahydroisoquinolines; WBC mobilization