Design of Annulated Pyrazoles as Inhibitors of HIV-1 Reverse Transcriptase

• Published in: Journal of medicinal chemistry Vol. 51; no. 23; pp. 7449 - 7458
• Main Authors: Sweeney, Zachary K, Harris, Seth F, Arora, Nidhi, Javanbakht, Hassan, Li, Yu, Fretland, Jennifer, Davidson, James P, Billedeau, J. Roland, Gleason, Shelley K, Hirschfeld, Donald, Kennedy-Smith, Joshua J, Mirzadegan, Taraneh, Roetz, Ralf, Smith, Mark, Sperry, Sarah, Suh, Judy M, Wu, Jeffrey, Tsing, Stan, Villaseñor, Armando G, Paul, Amber, Su, Guoping, Heilek, Gabrielle, Hang, Julie Q, Zhou, Amy S, Jernelius, Jesper A, Zhang, Fang-Jie, Klumpp, Klaus
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.12.2008; Amer Chemical Soc
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Biological and medical sciences; Cell Line, Transformed; Chemistry, Medicinal; Crystallography, X-Ray; Dogs; Drug Design; Haplorhini; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Hydrogen Bonding; Life Sciences & Biomedicine; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Science & Technology; Stereoisomerism; Structure-Activity Relationship; NONNUCLEOSIDE INHIBITORS; WILD-TYPE; POTENT; RT; ASSAY; STRUCTURAL BASIS; POSITIONAL ADAPTABILITY; FLEXIBILITY; COMPLEXES; DISCOVERY; Nitrile; RNA-directed DNA polymerase; Rat; HIV-1 virus; Non nucleoside compound; Monkey; Structure activity relation; Chlorine Organic compounds; Reverse transcriptase inhibitor; Primates; Binding mode; Antiviral; Benzonitrile derivatives; Dog; Clinical isolate; Fissipedia; Carnivora; Enzyme; Transferases; Rodentia; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Virus; Nucleotidyltransferases; Vertebrata; Mammalia; Animal; Etravirine; Human immunodeficiency virus; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800527x

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are recommended components of preferred combination antiretroviral therapies used for the treatment of HIV. These regimens are extremely effective in suppressing virus replication. Structure-based optimization of diaryl ether inhibitors led to the discovery of a new series of pyrazolo[3,4-c]pyridazine NNRTIs that bind the reverse transcriptase enzyme of human immunodeficiency virus-1 (HIV-RT) in an expanded volume relative to most other inhibitors in this class. The binding mode maintains the β13 and β14 strands bearing Pro236 in a position similar to that in the unliganded reverse transcriptase structure, and the distribution of interactions creates the opportunity for substantial resilience to single point mutations. Several pyrazolopyridazine NNRTIs were found to be highly effective against wild-type and NNRTI-resistant viral strains in cell culture.