title: Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists.
abstract: This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.
authors.affiliation: Sunesis Pharmaceuticals, Inc., 395 Oyster Point Blvd., South San Francisco, CA 94080, USA. mzhong@presidiopharma.com
authors.forename: Min
authors.initials: M
authors.lastname: Zhong
authors.forename: Wang
authors.initials: W
authors.lastname: Shen
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Barr
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Arbitrario
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Arkin
authors.forename: Minna
authors.initials: M
authors.lastname: Bui
authors.forename: Teresa
authors.initials: T
authors.lastname: Chen
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cunningham
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Evanchik
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Hanan
authors.forename: Ute
authors.initials: U
authors.lastname: Hoch
authors.forename: Karen
authors.initials: K
authors.lastname: Huen
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hyde
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kumer
authors.forename: Teresa
authors.initials: T
authors.lastname: Lac
authors.forename: Chris E
authors.initials: CE
authors.lastname: Lawrence
authors.forename: Jose R
authors.initials: JR
authors.lastname: Martell
authors.forename: Johan D
authors.initials: JD
authors.lastname: Oslob
authors.forename: Kumar
authors.initials: K
authors.lastname: Paulvannan
authors.forename: Saileta
authors.initials: S
authors.lastname: Prabhu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Silverman
authors.forename: Jasmin
authors.initials: J
authors.lastname: Wright
authors.forename: Chul H
authors.initials: CH
authors.lastname: Yu
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: W Mike
authors.initials: WM
authors.lastname: Flanagan
mesh_terms: D000818:Animals; D001682:Biological Availability; D055808:Drug Discovery; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D044005:Tetrahydroisoquinolines; D018799:Intercellular Adhesion Molecule-1