Lecture: Conformationally constrained peptido-mimetics

Abstract

Classic disadvantages of peptides as therapeutic agents are, for example, a poor metabolic stability due to proteolytic degradation, a rapid excretion through liver and kidneys, a limited bioavailability, etc…These inherent properties of peptides are caused by a high conformational freedom and reduced membrane permeability. To counter these limitations, and to enhance receptor selectivity and metabolic stability, constrained amino acids are widely used. The 4-amino-tetrahydro-2-benzazepinone scaffold 1 (Aba, Figure 1) mimics natural amino acids, such as Phe and Tyr. By limiting their c₁ space, the biologically active conformation is fixed. Similarly, 3-amino-indolo[2,3-c]azepinones of type 2 (Aia, Figure 1) serve as constrained Trp templates.

The introduction of 1 and 2 into biologically active peptides and its use as a priviledged template will be discussed. Moreover, the biological evaluation of azepine-containing peptides, the synthetic pathways to obtain substituted benzo- and indolo-azepines and the influence of ring substitution on the conformation and b-turn mimicry of 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one peptide mimetics, will be presented.