Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

按检索

Heterocycle amide isosteres: An approach to overcoming resistance for HIV-1 integrase strand transfer inhibitors

Institution:	1. National Taras Shevchenko University of Kyiv, Volodymyrska Street 64, Kyiv 01601, Ukraine;2. Curpys Chemicals, Teremkivska Street 2-A, Office 1, Kyiv 03187, Ukraine;1. Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad 431001, M.S., India;2. Department of Biotechnology, Savitribai Phule Pune University, Pune 411007, M.S., India;3. Shivaji University, Vidyanagar, Kolhapur 416 004, M.S., India;1. Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;2. Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States;3. Department of Computational-Aided Drug Design, Bristol-Myers Squibb Research and Development, Research Parkway, Wallingford, CT 06492, United States;4. Global Clinical Research, Bristol-Myers Squibb Research and Development, 5, Research Parkway, Wallingford, CT 06492, United States;1. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA;2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;3. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;4. Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;5. Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA;1. Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, Jiangsu, China;2. Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, 533-0024, Japan;3. Oakwood Chemical, Inc, 730 Columbia Hwy. N, Estill, SC, 29918, USA;4. Department of Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, PO Box, 4000, Princeton, NJ, 08543 4000, United States;5. Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018, San Sebastián, Spain;6. IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013, Bilbao, Spain

Abstract:	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.

Keywords:	HIV Integrase inhibitor HIV Integrase Strand transfer inhibitor Pyrimidinedione
本文献已被 ScienceDirect 等数据库收录！

设为首页 | 免责声明 | 关于勤云 | 加入收藏