Aminimides as Peptidomimetics

Abstract

Highly selective and specific protein-protein and peptide-protein interactions are elicited by a large number of natural specific biological responses. The mimicry of these natural interactions has been an important and useful strategy for the development of metabolically stable drugs capable of being administered orally (1-4). We report here on the use of a novel type of peptidomimetic based on the aminimide linkage. Aminimides are chemically described as hydrazinium hydroxide inner salts or as ammonium-imines. (Fig. 1) This unusual class of compounds possesses a zwitterionic nature that provides solubility in polar media (water, methanol, ethanol, acetonitrile, DMF, DMSO) as well as in nonpolar solvents such as benzene, when substituents are chosen to reduce the total molecular dipole moment. The aminimide bond has two resonance forms as shown in Fig. 1. ThepKa of the protonated form is generally less than 4. The predominant resonance form will place the formal negative charge on the more electronegative oxygen atom, although we typically use diagrams in which the formal charges reside on the two nitrogens to stress the absence of the hydrogen-bond-donating ability of the aminimide as compared the amide bond in peptides. The aminimide bond is extremely stable under both acidic and basic conditions and is highly resistant to proteolytic cleavage. Fig. 1. Resonance forms for trimethylammoniacetamidate.