Oxetanyl Peptides: Novel Peptidomimetic Modules for Medicinal Chemistry

ABSTRACT: The synthesis of novel oxetanyl peptides, where the amide bond is replaced by a non-hydrolyzable oxetanyl-amine fragment, is reported. This new class of pseudo-dipeptides with the same H-bond donor/acceptor pattern found in proteins expands the repertoire of peptidomimetics. With over 50 marketed drugs and an estimated $13 billionmarket in 2010, peptide drugs are important players in pharmaceuticals.1 This is however, a relatively small share of the total pharmaceuticals market given the broad range of biological activities displayed by this class of compounds. The discrepancy arises from some inherent limitations of peptides in the drug development process,1a,2 including short lifetimes in the stomach, intestine, and plasma, which often result in less than optimal pharmacokinetic profiles. However, the high specificity and potency as well as low toxicity of certain peptides along with advances in drug delivery have led to a renaissance.