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Diphenyl ether non-nucleoside reverse transcriptase inhibitors with excellent potency against resistant mutant viruses and promising pharmacokinetic properties. 2009
Zachary K Sweeney, and
Joshua J Kennedy-Smith, and
Jeffrey Wu, and
Nidhi Arora, and
J Roland Billedeau, and
James P Davidson, and
Jennifer Fretland, and
Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
Department of Medicinal Chemistry, Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. zachary.sweeney@roche.com
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are part of the preferred treatment regimens for individuals infected with HIV. These NNRTI-based regimens are efficacious, but the most popular NNRTIs have a low genetic barrier to resistance and have been associated with adverse events. There is therefore still a need for efficacious antiviral medicines that facilitate patient adherence and allow durable suppression of viral replication. As part of an extensive program targeted toward the discovery of NNRTIs that have favorable pharmacokinetic properties, good potency against NNRTI-resistant viruses, and a high genetic barrier to drug resistance, we focused on the optimization of a series of diaryl ether NNRTIs. In the course of this effort, we employed molecular modeling to design a new set of NNRTIs that that are active against wild-type HIV and key NNRTI-resistant mutant viruses. The structure-activity relationships observed in this series of compounds provide insight into the structural features required for NNRTIs that inhibit the replication of a wide range of mutant viruses. Selected compounds have promising pharmacokinetic profiles.
Related Publications
Zachary K Sweeney, and
Joshua J Kennedy-Smith, and
Jeffrey Wu, and
Nidhi Arora, and
J Roland Billedeau, and
James P Davidson, and
Jennifer Fretland, and
Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
November 2009,
Journal of medicinal chemistry,
Zachary K Sweeney, and
Joshua J Kennedy-Smith, and
Jeffrey Wu, and
Nidhi Arora, and
J Roland Billedeau, and
James P Davidson, and
Jennifer Fretland, and
Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
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Arzneimittel-Forschung,
Zachary K Sweeney, and
Joshua J Kennedy-Smith, and
Jeffrey Wu, and
Nidhi Arora, and
J Roland Billedeau, and
James P Davidson, and
Jennifer Fretland, and
Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
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Jeffrey Wu, and
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J Roland Billedeau, and
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Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
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Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
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Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
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Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
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Judy M Suh, and
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Klaus Klumpp
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Jennifer Fretland, and
Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
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Julie Q Hang, and
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Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
Guoping Su, and
Judy M Suh, and
Armando G Villaseñor, and
Michael Welch, and
Fang-Jie Zhang, and
Klaus Klumpp
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Jeffrey Wu, and
Nidhi Arora, and
J Roland Billedeau, and
James P Davidson, and
Jennifer Fretland, and
Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
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Judy M Suh, and
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Fang-Jie Zhang, and
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Nidhi Arora, and
J Roland Billedeau, and
James P Davidson, and
Jennifer Fretland, and
Julie Q Hang, and
Gabrielle M Heilek, and
Seth F Harris, and
Donald Hirschfeld, and
Petra Inbar, and
Hassan Javanbakht, and
Jesper A Jernelius, and
Qingwu Jin, and
Yu Li, and
Weiling Liang, and
Ralf Roetz, and
Keshab Sarma, and
Mark Smith, and
Dimitrio Stefanidis, and
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Judy M Suh, and
Armando G Villaseñor, and
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Fang-Jie Zhang, and
Klaus Klumpp
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