Phenethylthiazolylthiourea (PETT) Compounds as a New Class of HIV-1 Reverse Transcriptase Inhibitors. 2. Synthesis and Further Structure−Activity Relationship Studies of PETT Analogs
| Autor: | Mark A. Muesing, Robert Theodore Vasileff, Sahlberg C, Robert J. Ternansky, Cantrell As, C. L. Jordan, Jaskunas, L. Vrang, P. Engelhardt, Peter Thomas Lind, H. Zhang, Kinnick, R. Noreen, West Sj, Marita Högberg, Pranc P, J. Kangasmetsa, B. Oberg, N. G. Johansson, J. M. Jun. Morin |
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| Rok vydání: | 1996 |
| Předmět: |
chemistry.chemical_classification
biology Anti-HIV Agents Chemistry Stereochemistry Hydrochloride Thiourea Chemical synthesis HIV Reverse Transcriptase Intercalating Agents Reverse transcriptase Structure-Activity Relationship Thiazoles chemistry.chemical_compound Enzyme Enzyme inhibitor Trovirdine Drug Discovery biology.protein Animals Molecular Medicine Structure–activity relationship Cells Cultured |
| Zdroj: | Journal of Medicinal Chemistry. 39:4261-4274 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm950639r |
| Popis: | Phenylethylthiazolylthiourea (PETT) derivatives have been identified as a new series of non-nucleoside inhibitors of HIV-1 RT. Structure-activity relationship studies of this class of compounds resulted in the identification of N-[2-(2-pyridyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea hydrochloride (trovirdine; LY300046.HCl) as a highly potent anti-HIV-1 agent. Trovirdine is currently in phase one clinical trials for potential use in the treatment of AIDS. Extension of these structure-activity relationship studies to identify additional compounds in this series with improved properties is ongoing. A part of this work is described here. Replacement of the two aromatic moieties of the PETT compounds by various substituted or unsubstituted heteroaromatic rings was investigated. In addition, the effects of multiple substitution in the phenyl ring were also studied. The antiviral activities were determined on wild-type and constructed mutants of HIV-1 RT and on wild-type HIV-1 and mutant viruses derived thereof, Ile100 and Cys181, in cell culture assays. Some selected compounds were determined on double-mutant viruses, HIV-1 (Ile 100/Asn103) and HIV-1 (Ile100/Cys181). A number of highly potent analogs were synthesized. These compounds displayed IC50's against wild-type RT between 0.6 and 5 nM. In cell culture, these agents inhibited wild-type HIV-1 with ED50's between 1 and 5 nM in MT-4 cells. In addition, these derivatives inhibited mutant HIV-1 RT (Ile 100) with IC50's between 20 and 50 nM and mutant HIV-1 RT (Cys 181) with IC50's between 4 and 10 nM, and in cell culture they inhibited mutant HIV-1 (Ile100) with ED50's between 9 and 100 nM and mutant HIV-1 (Cys181) with ED50's between 3 and 20 nM. |
| Databáze: | OpenAIRE |
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