Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors
| Autor: | Tricia Protack, Michael A. Walker, Guo Li, David R. Langley, B. Narasimhulu Naidu, Nicholas A. Meanwell, George L. Trainor, Alicia Ng, Susan Jenkins, Mark Krystal, Zeyu Lin, Samuel Gerritz, Christopher Cianci, Hal A. Lewis, Kevin Kish, Javed Khan, Prasanna Sivaprakasam, Annapurna Pendri, Ira B. Dicker, Linda Discotto |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Pyridines Allosteric regulation Administration Oral HIV Infections HIV Integrase Pharmacology 01 natural sciences Pyrazolopyrimidine Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Allosteric Regulation Drug Discovery Animals Humans Transferase HIV Integrase Inhibitors Vector (molecular biology) 030304 developmental biology 0303 health sciences biology Chemistry Drug discovery virus diseases Active site 0104 chemical sciences Bioavailability Integrase Molecular Docking Simulation 010404 medicinal & biomolecular chemistry HIV-1 biology.protein Pyrazoles Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 63:2620-2637 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.9b01681 |
| Popis: | The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties. |
| Databáze: | OpenAIRE |
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