Neurodegenerative diseases (NDs) involving the central nervous system (CNS), such as Alzheimer (AD) and Parkinson (PD) diseases, affect millions of people worldwide and represent a real challenge for the future societies. Considering the absence of effective pharmaceuticals to cope with the neurodegenerative processes, the quest for effective neuroprotective molecules remains a major goal to support the clinical response towards NDs.

Glypromate® is a short peptide obtained by N-terminal cleavage of oxytocin hormone mediated by acid proteases. This neuropeptide displays neuroprotective activity within the CNS in many in vitro and in vivo animal models of NDs, and therefore is of utmost relevance for the development of neuroprotective drugs. However, recent clinical trials conducted for this peptide by Neuren Pharmaceuticals failed due to inefficient oral absorption.

In this work, we aimed at the rescuing of Glypromate® by the development of a bioinspired strategy to overcome the low absorption profile associated to this peptide. Since Glypromate® is metabolized by carboxypeptidases, the appropriated amino acid residue for conjugation with lipophilic active pharmaceutical ingredients (APIs) is glutamate, which may allow the release of both APIs and the native peptide. Moreover, this strategy may also provide a means to explore neuroprotective synergism and potentiate the permeability across the blood-brain barrier, potentiating their pharmacological action. For this purpose, small bioactive amines were selected as appropriated APIs for conjugation considering their high lipophilicity and relevance in clinic as therapeutics in the treatment of NDs. In so doing, twelve novel conjugates were synthesized and biologically evaluated.