Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor
| Autor: | Richard J. Hazen, George Andrew Freeman, Karen Rene Romines, Joseph H. Chan, Jill R. Cowan, Jeffrey H. Tidwell, Steven A. Short, Andrews Clarence Webster, Robert G. Ferris, Lee T. Schaller, David K. Stammers, Steve S. Gonzales, Lawrence R. Boone |
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| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Předmět: |
Cyclopropanes
Male Nevirapine Efavirenz Anti-HIV Agents Drug resistance Biology Virus Cell Line Benzophenones Structure-Activity Relationship chemistry.chemical_compound Dogs Drug Resistance Viral Nitriles Oxazines Drug Discovery medicine Animals Humans Sulfonamides Reverse-transcriptase inhibitor Wild type virus diseases biology.organism_classification Virology HIV Reverse Transcriptase Benzoxazines Macaca fascicularis chemistry Enzyme inhibitor Alkynes Mutation Lentivirus HIV-1 biology.protein Reverse Transcriptase Inhibitors Molecular Medicine medicine.drug |
| Zdroj: | J Med Chem. 49(2) |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Despite the progress of the past two decades, there is still considerable need for safe, efficacious drugs that target human immunodeficiency virus (HIV). This is particularly true for the growing number of patients infected with virus resistant to currently approved HIV drugs. Our high throughput screening effort identified a benzophenone template as a potential nonnucleoside reverse transcriptase inhibitor (NNRTI). This manuscript describes our extensive exploration of the benzophenone structure-activity relationships, which culminated in the identification of several compounds with very potent inhibition of both wild type and clinically relevant NNRTI-resistant mutant strains of HIV. These potent inhibitors include 70h (GW678248), which has in vitro antiviral assay IC(50) values of 0.5 nM against wild-type HIV, 1 nM against the K103N mutant associated with clinical resistance to efavirenz, and 0.7 nM against the Y181C mutant associated with clinical resistance to nevirapine. Compound 70h has also demonstrated relatively low clearance in intravenous pharmacokinetic studies in three species, and it is the active component of a drug candidate which has progressed to phase 2 clinical studies. |
| Databáze: | OpenAIRE |
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