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Diphenyl Ether Non‐Nucleoside Reverse Transcriptase Inhibitors with Excellent Potency Against Resistant Mutant Viruses and Promising Pharmacokinetic Properties
Author(s) -
Sweeney Zachary K.,
KennedySmith Joshua J.,
Wu Jeffrey,
Arora Nidhi,
Billedeau J. Roland,
Davidson James P.,
Fretland Jennifer,
Hang Julie Q.,
Heilek Gabrielle M.,
Harris Seth F.,
Hirschfeld Donald,
Inbar Petra,
Javanbakht Hassan,
Jernelius Jesper A.,
Jin Qingwu,
Li Yu,
Liang Weiling,
Roetz Ralf,
Sarma Keshab,
Smith Mark,
Stefanidis Dimitrio,
Su Guoping,
Suh Judy M.,
Villaseñor Armando G.,
Welch Michael,
Zhang FangJie,
Klumpp Klaus
Publication year - 2009
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200800262
Subject(s) - reverse transcriptase , nucleoside reverse transcriptase inhibitor , virology , pharmacokinetics , mutant , potency , biology , reverse transcriptase inhibitor , human immunodeficiency virus (hiv) , chemistry , pharmacology , in vitro , rna , antiretroviral therapy , viral load , biochemistry , gene
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.