Azepinone-constrained Amino Acids in Peptide And Peptidomimetic Design

Steven Ballet, Karel Jules Guillemyn, Olivier Van Der Poorten, Ben Schurgers, Guido Verniest, Dirk Tourwe

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

Abstract

Side chain topography of amino acids that are part of a peptide’s pharmacophore represents a crucial structural feature in peptidomimetic design. Constraining the side chain dihedral angles (χ angles) may limit the number of low energy conformations and lead to more potent, receptor subtype selective and enzymatically stable peptide ligands. The current chapter describes this strategy for aromatic amino acids such as Phe, Tyr, Trp, and His. The side chains of these residues are incorporated in or mimicked by amino-arylazepinones. A selection of synthetic pathways that were used and developed by our laboratory is described for obtaining conformationally constrained 4-amino-(7-hydroxy)-2-benzazepinones [Aba (or Hba)] and the corresponding amino-indolo- and amino-triazoloazepinones (Aia and Ata, respectively). These azepinone mimics were synthesized from amino acid educts and have been used in various biological applications. Moreover, other heterocyclic amino-azepinones were prepared based on ring-closing metathesis and post-cyclization modifications. Further elaboration of the substitution patterns in these azepinones has rendered them highly versatile building blocks for use in peptidomimetic design. The selected biological applications illustrate their potential for the development of novel peptide-based pharmacological probes and drug candidates
Original languageEnglish
Title of host publicationAzepinone-constrained Amino Acids in Peptide And Peptidomimetic Design
Publication statusPublished - 2015

Keywords

  • 4-Amino-2-arylazepinones – Angiotensin IV – Bradykinin – Conformationally constrained amino acids – Melanocortin – Opioid peptides – Somatostatin

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