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Issue 48, 2020
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Bioinspired design for the assembly of Glypromate® neuropeptide conjugates with active pharmaceutical ingredients

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Abstract

Neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, are a class of heterogeneous pathologies of the central nervous system (CNS) affecting millions of people worldwide. CNS-related pathologies represent a global health burden in developed and developing countries with no curative treatments currently available. Thus, the development of novel multitarget neuroprotective drugs is a health priority. In this work, a bioinspired methodology in solution-phase for the assembly and regioselective conjugation of Glypromate® neuropeptide with active pharmaceutical ingredients (APIs) is described. The main purpose is to design new hybrid molecules which may offer increased systemic resistance of Glypromate® towards proteases and/or allow the controlled release of both APIs and the neuroprotective peptide within CNS. For the synthesis of such peptide-hybrid compounds (R)-1-aminoindane, amantadine, and memantine were selected as APIs for conjugation with Glypromate®. Furthermore, capping strategies are explored to prepare Glypromate® conjugates with more favorable pharmacodynamic profiles by masking polar exposed groups. Overall, this synthetic approach led to the development of a small library of 12 conjugates with improved drug-like properties in comparison with Glypromate®, paving the way for the discovery of novel CNS multitarget drugs. Additionally, by exploring the bis-functionalization of glutamate, the formation of chiral glutarimides is disclosed for the first time employing TBTU as the coupling reagent. This unusual reactivity of TBTU with glutamate offers a new synthetic approach for the preparation of chiral glutarimide alkaloids.

Graphical abstract: Bioinspired design for the assembly of Glypromate® neuropeptide conjugates with active pharmaceutical ingredients

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Supplementary files

Article information


Submitted
02 Oct 2020
Accepted
20 Nov 2020
First published
20 Nov 2020

New J. Chem., 2020,44, 21049-21063
Article type
Paper

Bioinspired design for the assembly of Glypromate® neuropeptide conjugates with active pharmaceutical ingredients

S. C. Silva-Reis, A. C. V. D. dos Santos, X. García-Mera, J. E. Rodríguez-Borges and I. E. Sampaio-Dias, New J. Chem., 2020, 44, 21049
DOI: 10.1039/D0NJ04851H

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