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ID: ALA4706543
Journal: Eur J Med Chem
Title: Discovery of the first potent and selective αβ integrin inhibitor based on an amide-containing core.
Authors: Lippa RA,Barrett J,Pal S,Rowedder JE,Murphy JA,Barrett TN
Abstract: Integrins αβ and αβ are closely related, proangiogenic members of the wider RGD-binding integrin family. Due to their high sequence homology, the development of αβ-selective compounds has remained elusive to synthetic and medicinal chemists. Herein, we describe a survey of SAR around a series of amide-containing 3-aryl-succinamic acid-based RGD mimetics. This resulted in the discovery of α,α,α-trifluorotolyl 12 which exhibits 800 × selectivity for αβversus αβ with a pyrrolidine amide linker that confers selectivity for αβ by positioning a key aryl ring in the SDL of αβ with good complementarity; binding in this mode is disfavoured in αβ due to clashes with key residues in the β-subunit. Compound 12 exhibits selective inhibition by a cell adhesion assay, high passive permeability and solubility which enables potential use of this inhibitor as an αβ-selective in vitro tool compound.
CiteXplore: 32865176