title: N-Benzoyl amino acids as ICAM/LFA-1 inhibitors. Part 2: structure-activity relationship of the benzoyl moiety.
abstract: o-Bromobenzoyl l-tryptophan 1 inhibits the association of LFA-1 with ICAM-1 with an IC(50) of 1.7microM. Evaluation of the structure-activity relationship of the benzoyl moiety shows that 2,6-di-substitutions greatly enhance potency of this class of inhibitors. Electronegative substitutions that favor a 90 degrees angle between the benzoyl ring and the amide bond yield the most potent compounds. There is a strong correlation between the potency of the compounds and the difference between the ab initio energy at 90 degrees and the global minima energy for given compounds. Combining the favored benzoyl substitutions with l-histidine and l-asparagine resulted in a 15-fold increase in potency over compound 1.
authors.affiliation: Department of Medicinal Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, CA 94080, USA. burdick.dan@gene.com
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Burdick
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: Ignacio
authors.initials: I
authors.lastname: Aliagas-Martin
authors.forename: Mark
authors.initials: M
authors.lastname: Stanley
authors.forename: Maureen
authors.initials: M
authors.lastname: Beresini
authors.forename: Kevin
authors.initials: K
authors.lastname: Clark
authors.forename: Robert S
authors.initials: RS
authors.lastname: McDowell
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Gadek
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1