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Article

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

Angelini Pharma S.p.A., Viale Amelia, 70, 00181 Rome, Italy
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Author to whom correspondence should be addressed.
Academic Editor: Maria Cristina De Rosa
Molecules 2020, 25(9), 2163; https://doi.org/10.3390/molecules25092163
Received: 14 April 2020 / Revised: 30 April 2020 / Accepted: 2 May 2020 / Published: 5 May 2020
(This article belongs to the Special Issue Drug Discovery and Molecular Docking)
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 16, 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 (718) to overcome such liability. In detail, structure-based approaches and fine-tuning of physicochemical properties guided the design of derivatives 718 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 16. 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. View Full-Text
Keywords: glycogen synthase kinase-3β (GSK-3β); 1H-indazole-3-carboxamide core (INDZ); imidazo[1,5-a]pyridine-1-carboxamide core (IMID 1); imidazo[1,5-a]pyridine-3-carboxamide core (IMID 2); CNS permeability; molecular docking; molecular dynamics (MD); quantum mechanics (QM); X-ray crystallography; NMR characterization glycogen synthase kinase-3β (GSK-3β); 1H-indazole-3-carboxamide core (INDZ); imidazo[1,5-a]pyridine-1-carboxamide core (IMID 1); imidazo[1,5-a]pyridine-3-carboxamide core (IMID 2); CNS permeability; molecular docking; molecular dynamics (MD); quantum mechanics (QM); X-ray crystallography; NMR characterization
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MDPI and ACS Style

Buonfiglio, R.; Prati, F.; Bischetti, M.; Cavarischia, C.; Furlotti, G.; Ombrato, R. Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches. Molecules 2020, 25, 2163. https://doi.org/10.3390/molecules25092163

AMA Style

Buonfiglio R, Prati F, Bischetti M, Cavarischia C, Furlotti G, Ombrato R. Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches. Molecules. 2020; 25(9):2163. https://doi.org/10.3390/molecules25092163

Chicago/Turabian Style

Buonfiglio, Rosa, Federica Prati, Martina Bischetti, Claudia Cavarischia, Guido Furlotti, and Rosella Ombrato. 2020. "Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches" Molecules 25, no. 9: 2163. https://doi.org/10.3390/molecules25092163

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