title: Design of LFA-1 antagonists based on a 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold.
abstract: A new class of lymphocyte function-associated antigen-1 (LFA-1) antagonists is described. Elaboration of the 2,3-dihydro-1H-pyrrolizin-5(7aH)-one scaffold resulted in the synthesis of potent inhibitors of the LFA-1/ICAM-1 interaction. Along with the in vitro activity, we present the X-ray crystal structure of the complex of compound 9b, in a novel binding mode to the I-domain of LFA-1.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543-4000, USA. dharmpal.dodd@bms.com
authors.forename: Dharmpal S
authors.initials: DS
authors.lastname: Dodd
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: ChiehYing J
authors.initials: CJ
authors.lastname: Chang
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Stetsko
authors.forename: Linda M
authors.initials: LM
authors.lastname: Phillips
authors.forename: Yingru
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michele
authors.initials: M
authors.lastname: Launay
authors.forename: Dominique
authors.initials: D
authors.lastname: Potin
authors.forename: Wayne
authors.initials: W
authors.lastname: Vaccaro
authors.forename: Michael A
authors.initials: MA
authors.lastname: Poss
authors.forename: Murray
authors.initials: M
authors.lastname: McKinnon
authors.forename: Joel C
authors.initials: JC
authors.lastname: Barrish
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Suchard
authors.forename: T G
authors.initials: TG
authors.lastname: Murali Dhar
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry*; D008956:Models, Chemical; D008968:Molecular Conformation; D011758:Pyrroles / Q000737:chemistry*; D013237:Stereoisomerism; D013696:Temperature; D014965:X-Rays
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D011758:Pyrroles