N1-Heterocyclic pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase

• Published in: Bioorganic & medicinal chemistry letters 2010-03, Vol.20 (5), p.1585-1588
• Main Authors: Mitchell, Michael L., Son, Jong Chan, Lee, Ill Young, Lee, Chong-Kyo, Kim, Hae Soo, Guo, Hongyan, Wang, Jianhong, Hayes, Jaclyn, Wang, Michael, Paul, Amber, Lansdon, Eric B., Chen, James M., Eisenberg, Gene, Geleziunas, Romas, Xu, Lianhong, Kim, Choung U.
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacokinetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antibodies; Antiviral agents; Binding Sites; Biological and medical sciences; Crystallography, X-Ray; Dogs; Heterocyclic Compounds - chemistry; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Hydrogen Bonding; Medical sciences; Microsomes - metabolism; Mutant Proteins - antagonists & inhibitors; Mutant Proteins - metabolism; Non-nucleoside; Pharmacology. Drug treatments; Pyrimidinedione; Pyrimidinones - chemical synthesis; Pyrimidinones - chemistry; Pyrimidinones - pharmacokinetics; Reverse transcriptase; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacokinetics; Structure-Activity Relationship; Thymine - analogs & derivatives; Thymine - chemical synthesis; Thymine - chemistry; Thymine - pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.086

A series of N1-heterocyclic pyrimidinediones were evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors, resulting in the discovery of compound 13. A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.