title: Solid-phase synthesis of dual alpha4beta1/alpha4beta7 integrin antagonists: two scaffolds with overlapping pharmacophores.
abstract: Two structural classes of dual alpha4beta1/alpha4beta7 integrin antagonists were investigated via solid-phase parallel synthesis. Using an acylated amino acid backbone, lead compounds containing biphenylalanine or tyrosine carbamate scaffolds were optimized for inhibition of alpha4beta1/VCAM and alpha4beta7/MAdCAM. A comparison of the structure-activity relationships in the inhibition of the alpha4beta7/MAdCAM interaction for substituted amines employed in both scaffolds suggests a similar binding mode for the compounds.
authors.affiliation: Department of Bioorganic Chemistry, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Castanedo
authors.forename: Fredrick C
authors.initials: FC
authors.lastname: Sailes
authors.forename: Nathan J P
authors.initials: NJ
authors.lastname: Dubree
authors.forename: John B
authors.initials: JB
authors.lastname: Nicholas
authors.forename: Lisa
authors.initials: L
authors.lastname: Caris
authors.forename: Kevin
authors.initials: K
authors.lastname: Clark
authors.forename: Susan M
authors.initials: SM
authors.lastname: Keating
authors.forename: Maureen H
authors.initials: MH
authors.lastname: Beresini
authors.forename: Henry
authors.initials: H
authors.lastname: Chiu
authors.forename: Sherman
authors.initials: S
authors.lastname: Fong
authors.forename: James C
authors.initials: JC
authors.lastname: Marsters
authors.forename: David Y
authors.initials: DY
authors.lastname: Jackson
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sutherlin
mesh_terms: D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: D007202:Indicators and Reagents; D039041:Integrin alpha4beta1; D016023:Integrins; C071777:integrin alpha4beta7