Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV
Autor: | Jay A. Grobler, Abbas Walji, Paul J. Coleman, Min Xu, Timothy J. Hartingh, Natasa Pajkovic, John T. Sisko, David A. Powell, John M. Sanders, Michael D. Miller, Mark Embrey, Rada Vanessa L, Keith P. Moore, Daniel J. Klein, Nguyen Natalie, Izzat T. Raheem, Dubost David C, Guillaume Barbe, Louis-Charles Campeau, Daria J. Hazuda, John S. Wai, Thomas G. Steele, John D. Schreier, Jamie M. McCabe Dunn |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Pyridones Clinical Biochemistry Human immunodeficiency virus (HIV) Pharmaceutical Science Integrase inhibitor HIV Infections HIV Integrase Pharmacology medicine.disease_cause 01 natural sciences Biochemistry Strand transfer 03 medical and health sciences chemistry.chemical_compound Dogs Drug Discovery medicine Animals Humans Structure–activity relationship HIV Integrase Inhibitors Molecular Biology biology Organic Chemistry Raltegravir 0104 chemical sciences Integrase Molecular Docking Simulation 010404 medicinal & biomolecular chemistry 030104 developmental biology chemistry HIV-1 Aminal biology.protein Molecular Medicine Lead compound medicine.drug |
Zdroj: | Bioorganic & Medicinal Chemistry Letters. 27:2038-2046 |
ISSN: | 0960-894X |
Popis: | HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction. |
Databáze: | OpenAIRE |
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