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ID: ALA1133808
Journal: Bioorg Med Chem Lett
Title: The discovery of sulfonylated dipeptides as potent VLA-4 antagonists.
Authors: Hagmann WK, Durette PL, Lanza T, Kevin NJ, de Laszlo SE, Kopka IE, Young D, Magriotis PA, Li B, Lin LS, Yang G, Kamenecka T, Chang LL, Wilson J, MacCoss M, Mills SG, Van Riper G, McCauley E, Egger LA, Kidambi U, Lyons K, Vincent S, Stearns R, Colletti A, Teffera J, Tong S, Fenyk-Melody J, Owens K, Levorse D, Kim P, Schmidt JA, Mumford RA.
Abstract: Directed screening of a carboxylic acid-containing combinatorial library led to the discovery of potent inhibitors of the integrin VLA-4. Subsequent optimization by solid-phase synthesis afforded a series of sulfonylated dipeptide inhibitors with structural components that when combined in a single hybrid molecule gave a sub-nanomolar inhibitor as a lead for medicinal chemistry. Preliminary metabolic studies led to the discovery of substituted biphenyl derivatives with low picomolar activities. SAR and pharmacokinetic characterization of this series are presented.
CiteXplore: 11591507