title: Specific and dual antagonists of alpha(4)beta(1) and alpha(4)beta(7) integrins.
abstract: N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the alpha(4)beta(1) integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for alpha(4)beta(1) and alpha(4)beta(7) is proposed to explain the structure-activity relationship.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. linus_lin@merck.com
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Thomas
authors.initials: T
authors.lastname: Lanza
authors.forename: Ermenegilda
authors.initials: E
authors.lastname: McCauley
authors.forename: Gail
authors.initials: G
authors.lastname: Van Riper
authors.forename: Usha
authors.initials: U
authors.lastname: Kidambi
authors.forename: Jin
authors.initials: J
authors.lastname: Cao
authors.forename: Linda A
authors.initials: LA
authors.lastname: Egger
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: John A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D039041:Integrin alpha4beta1; D016023:Integrins; C449666:N-(3,5-dichlorophenylsulfonyl)-thioprolyl biarylalanine; D016201:Receptors, Lymphocyte Homing; D013438:Sulfhydryl Compounds; C071777:integrin alpha4beta7; D000409:Alanine