Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors
| Autor: | Michael A. Walker, Kevin M. Peese, Volodymyr Gali, Himadri Samanta, Manoj Patel, Ming Zheng, David R. Langley, B. Narasimhulu Naidu, Chen Li, Tricia Protack, Ira B. Dicker, Susan Jenkins, Zeyu Lin, Nicholas A. Meanwell, Brian Terry, Mark Krystal |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Clinical Biochemistry Pharmaceutical Science Integrase inhibitor HIV Integrase Molecular Dynamics Simulation 01 natural sciences Biochemistry chemistry.chemical_compound Structure-Activity Relationship Amide Catalytic Domain Drug Discovery Drug Resistance Viral medicine Pyrimidinedione Moiety Animals Humans HIV Integrase Inhibitors Molecular Biology chemistry.chemical_classification Binding Sites biology 010405 organic chemistry Elvitegravir Organic Chemistry Raltegravir Amides 0104 chemical sciences Integrase Rats 010404 medicinal & biomolecular chemistry chemistry Mutation biology.protein HIV-1 Molecular Medicine Azole Heterocyclic Compounds 3-Ring medicine.drug Half-Life |
| Zdroj: | Bioorganicmedicinal chemistry letters. 30(3) |
| ISSN: | 1464-3405 |
| Popis: | A series of heterocyclic pyrimidinedione-based HIV-1 integrase inhibitors was prepared and screened for activity against purified integrase enzyme and/or viruses modified with the following mutations within integrase: Q148R, Q148H/G140S and N155H. These are mutations that result in resistance to the first generation integrase inhibitors raltegravir and elvitegravir. Based on consideration of drug-target interactions, an approach was undertaken to replace the amide moiety of the first generation pyrimidinedione inhibitor with azole heterocycles that could retain potency against these key resistance mutations. An imidazole moiety was found to be the optimal amide substitute and the observed activity was rationalized with the use of calculated properties and modeling. Rat pharmacokinetic (PK) studies of the lead imidazole compounds demonstrated moderate clearance and moderate exposure. |
| Databáze: | OpenAIRE |
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