Novel Benzophenones as Non-nucleoside Reverse Transcriptase Inhibitors of HIV-1

• Published in: Journal of medicinal chemistry Vol. 47; no. 5; pp. 1175 - 1182
• Main Authors: Chan, Joseph H, Freeman, George A, Tidwell, Jeffrey H, Romines, Karen R, Schaller, Lee T, Cowan, Jill R, Gonzales, Steve S, Lowell, Gina S, Andrews, C. W, Reynolds, David J, St Clair, Marty, Hazen, Richard J, Ferris, Rob G, Creech, Katrina L, Roberts, Grace B, Short, Steven A, Weaver, Kurt, Koszalka, George W, Boone, Lawrence R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.02.2004; Amer Chemical Soc
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Benzophenones - chemical synthesis; Benzophenones - chemistry; Benzophenones - pharmacology; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Crystallography, X-Ray; Drug Resistance, Viral; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Humans; Inhibitory Concentration 50; Life Sciences & Biomedicine; Medical sciences; Mutation; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Protein Binding; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; TRIAL; POTENT; REPLICATION; ZIDOVUDINE; RESISTANCE; INFECTION; NEVIRAPINE; Benzophenone derivatives; Sulfonamide; HIV-1 virus; Non nucleoside compound; Benzene derivatives; Retroviridae; Lentivirus; Ketone; In vitro; Virus; Structure activity relation; Chlorine Organic compounds; Reverse transcriptase inhibitor; Antiviral; Fluorine Organic compounds; Human immunodeficiency virus; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030255y

GW4511, GW4751, and GW3011 showed IC50 values ≤2 nM against wild type HIV-1 and <10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.