Cargando…

Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches

The interest of research groups and pharmaceutical companies to discover novel GSK-3β inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) deriva...

Descripción completa

Detalles Bibliográficos
Autores principales: Buonfiglio, Rosa, Prati, Federica, Bischetti, Martina, Cavarischia, Claudia, Furlotti, Guido, Ombrato, Rosella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248956/
https://www.ncbi.nlm.nih.gov/pubmed/32380735
http://dx.doi.org/10.3390/molecules25092163
_version_ 1783538491408252928
author Buonfiglio, Rosa
Prati, Federica
Bischetti, Martina
Cavarischia, Claudia
Furlotti, Guido
Ombrato, Rosella
author_facet Buonfiglio, Rosa
Prati, Federica
Bischetti, Martina
Cavarischia, Claudia
Furlotti, Guido
Ombrato, Rosella
author_sort Buonfiglio, Rosa
collection PubMed
description The interest of research groups and pharmaceutical companies to discover novel GSK-3β inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) derivatives 1–6, showing good GSK-3β inhibition activity. However, they suffered from generally poor central nervous system (CNS) permeability. Here, we describe the design, synthesis, and in vitro characterization of novel imidazo[1,5-a]pyridine-1-carboxamide (IMID 1) and imidazo[1,5-a]pyridine-3-carboxamide (IMID 2) compounds (7–18) to overcome such liability. In detail, structure-based approaches and fine-tuning of physicochemical properties guided the design of derivatives 7–18 resulting in ameliorated absorption, distribution, metabolism, and excretion (ADME) properties. A crystal structure of 16 in complex with GSK-3β enzyme (PDB entry 6Y9S) confirmed the in silico models. Despite the nanomolar inhibition activity, the new core compounds showed a reduction in potency with respect to INDZ derivatives 1–6. In this context, Molecular Dynamics (MD) and Quantum Mechanics (QM) based approaches along with NMR investigation helped to rationalize the observed structure activity relationship (SAR). With these findings, the key role of the acidic hydrogen of the central core for a tight interaction within the ATP pocket of the enzyme reflecting in good GSK-3β affinity was demonstrated.
format Online
Article
Text
id pubmed-7248956
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-72489562020-06-10 Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches Buonfiglio, Rosa Prati, Federica Bischetti, Martina Cavarischia, Claudia Furlotti, Guido Ombrato, Rosella Molecules Article The interest of research groups and pharmaceutical companies to discover novel GSK-3β inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) derivatives 1–6, showing good GSK-3β inhibition activity. However, they suffered from generally poor central nervous system (CNS) permeability. Here, we describe the design, synthesis, and in vitro characterization of novel imidazo[1,5-a]pyridine-1-carboxamide (IMID 1) and imidazo[1,5-a]pyridine-3-carboxamide (IMID 2) compounds (7–18) to overcome such liability. In detail, structure-based approaches and fine-tuning of physicochemical properties guided the design of derivatives 7–18 resulting in ameliorated absorption, distribution, metabolism, and excretion (ADME) properties. A crystal structure of 16 in complex with GSK-3β enzyme (PDB entry 6Y9S) confirmed the in silico models. Despite the nanomolar inhibition activity, the new core compounds showed a reduction in potency with respect to INDZ derivatives 1–6. In this context, Molecular Dynamics (MD) and Quantum Mechanics (QM) based approaches along with NMR investigation helped to rationalize the observed structure activity relationship (SAR). With these findings, the key role of the acidic hydrogen of the central core for a tight interaction within the ATP pocket of the enzyme reflecting in good GSK-3β affinity was demonstrated. MDPI 2020-05-05 /pmc/articles/PMC7248956/ /pubmed/32380735 http://dx.doi.org/10.3390/molecules25092163 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Buonfiglio, Rosa
Prati, Federica
Bischetti, Martina
Cavarischia, Claudia
Furlotti, Guido
Ombrato, Rosella
Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches
title Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches
title_full Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches
title_fullStr Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches
title_full_unstemmed Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches
title_short Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches
title_sort discovery of novel imidazopyridine gsk-3β inhibitors supported by computational approaches
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248956/
https://www.ncbi.nlm.nih.gov/pubmed/32380735
http://dx.doi.org/10.3390/molecules25092163
work_keys_str_mv AT buonfigliorosa discoveryofnovelimidazopyridinegsk3binhibitorssupportedbycomputationalapproaches
AT pratifederica discoveryofnovelimidazopyridinegsk3binhibitorssupportedbycomputationalapproaches
AT bischettimartina discoveryofnovelimidazopyridinegsk3binhibitorssupportedbycomputationalapproaches
AT cavarischiaclaudia discoveryofnovelimidazopyridinegsk3binhibitorssupportedbycomputationalapproaches
AT furlottiguido discoveryofnovelimidazopyridinegsk3binhibitorssupportedbycomputationalapproaches
AT ombratorosella discoveryofnovelimidazopyridinegsk3binhibitorssupportedbycomputationalapproaches