title: Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intracellular adhesion molecule-1 interaction. 1. Identification of an additional binding pocket based on an anilino diaryl sulfide lead.
abstract: The interaction between leukocyte function-associated antigen-1 (LFA-1), a member of the beta(2)-integrin family of adhesion molecules, and intracellular adhesion molecule ICAM-1 (cd54) is thought to play a critical role in the inflammatory process. On the basis of an anilino diaryl sulfide screening lead 1, in combination with pharmacophore analysis of other screening hits, we have identified an adjacent binding pocket. Subsequently, a p-ethenylcarbonyl linker was discovered to be optimal for accessing this binding site. Solution-phase parallel synthesis enabled rapid optimization of the cinnamides for this pocket. In conjunction with fine-tuning of the diaryl substituents, we discovered a novel series of potent, nonpeptide inhibitors of LFA-1/ICAM-1 interaction, exemplified by A-286982 (28h), which has IC(50) values of 44 and 35 nM in an LFA-1/ICAM-1 binding assay and LFA-1-mediated cellular adhesion assay, respectively.
authors.affiliation: Metabolic Disease Research and Drug Analysis Department, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA. Gang.Liu@abbott.com
authors.forename: G
authors.initials: G
authors.lastname: Liu
authors.forename: J T
authors.initials: JT
authors.lastname: Link
authors.forename: Z
authors.initials: Z
authors.lastname: Pei
authors.forename: E B
authors.initials: EB
authors.lastname: Reilly
authors.forename: S
authors.initials: S
authors.lastname: Leitza
authors.forename: B
authors.initials: B
authors.lastname: Nguyen
authors.forename: K C
authors.initials: KC
authors.lastname: Marsh
authors.forename: G F
authors.initials: GF
authors.lastname: Okasinski
authors.forename: T W
authors.initials: TW
authors.lastname: von Geldern
authors.forename: M
authors.initials: M
authors.lastname: Ormes
authors.forename: K
authors.initials: K
authors.lastname: Fowler
authors.forename: M
authors.initials: M
authors.lastname: Gallatin
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology; D001665:Binding Sites; D001682:Biological Availability; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism*; D008297:Male; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D010879:Piperazines; D013440:Sulfides; D018799:Intercellular Adhesion Molecule-1; C415578:A 286982