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Solid-phase synthesis of dual α4β1/α4β7 integrin antagonists: two scaffolds with overlapping pharmacophores

2002; Elsevier BV; Volume: 12; Issue: 20 Linguagem: Inglês

10.1016/s0960-894x(02)00597-8

1464-3405

Georgette M. Castanedo, Fredrick C. Sailes, N. Dubree, John B. Nicholas, Lisa D. Caris, Kevin Clark, Susan M. Keating, Maureen H. Beresini, Henry Chiu, Sherman Fong, James C. Marsters, David Y. Jackson, Daniel P. Sutherlin,

Monoclonal and Polyclonal Antibodies Research

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.