Design and Synthesis of Novel N-Hydroxy-Dihydronaphthyridinones as Potent and Orally Bioavailable HIV-1 Integrase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 54; no. 9; pp. 3393 - 3417
• Main Authors: Johnson, Ted W, Tanis, Steven P, Butler, Scott L, Dalvie, Deepak, DeLisle, Dorothy M, Dress, Klaus R, Flahive, Erik J, Hu, Qiyue, Kuehler, Jon E, Kuki, Atsuo, Liu, Wen, McClellan, Guy A, Peng, Qinghai, Plewe, Michael B, Richardson, Paul F, Smith, Graham L, Solowiej, Jim, Tran, Khanh T, Wang, Hai, Yu, Xiaoming, Zhang, Junhu, Zhu, Huichun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.05.2011; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Biological Availability; Cell Membrane Permeability; Cells, Cultured; Chemistry, Medicinal; Dogs; Drug Design; Hepatocytes - metabolism; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - pharmacology; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - pharmacokinetics; HIV Integrase Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Life Sciences & Biomedicine; Liver - metabolism; Molecular Conformation; Naphthyridines - chemical synthesis; Naphthyridines - pharmacokinetics; Naphthyridines - pharmacology; Pharmacology & Pharmacy; Science & Technology; Structure-Activity Relationship; LIGAND; RALTEGRAVIR; VIRUS TYPE-1 INTEGRASE; DISCOVERY; REVERSE-TRANSCRIPTASE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200208d

HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.