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Title: Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses

Abstract

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.

Authors:
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  1. Merck
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE
OSTI Identifier:
1007124
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 51; Journal Issue: (20) ; 10, 2008; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ENZYME INHIBITORS; NITRILES; ORGANIC CHLORINE COMPOUNDS; AIDS VIRUS; MUTATIONS; PHYSICAL PROPERTIES; THERAPY

Citation Formats

Tucker, Thomas J, Sisko, John T, Tynebor, Robert M, Williams, Theresa M, Felock, Peter J, Flynn, Jessica A, Lai, Ming-Tain, Liang, Yuexia, McGaughey, Georgia, Liu, Meiquing, Miller, Mike, Moyer, Gregory, Munshi, Vandna, Perlow-Poehnelt, Rebecca, Prasad, Sridhar, Reid, John C, Sanchez, Rosa, Torrent, Maricel, Vacca, Joseph P, Wan, Bang-Lin, and Yan, Youwei. Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses. United States: N. p., 2009. Web. doi:10.1021/jm800856c.
Tucker, Thomas J, Sisko, John T, Tynebor, Robert M, Williams, Theresa M, Felock, Peter J, Flynn, Jessica A, Lai, Ming-Tain, Liang, Yuexia, McGaughey, Georgia, Liu, Meiquing, Miller, Mike, Moyer, Gregory, Munshi, Vandna, Perlow-Poehnelt, Rebecca, Prasad, Sridhar, Reid, John C, Sanchez, Rosa, Torrent, Maricel, Vacca, Joseph P, Wan, Bang-Lin, & Yan, Youwei. Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses. United States. doi:10.1021/jm800856c.
Tucker, Thomas J, Sisko, John T, Tynebor, Robert M, Williams, Theresa M, Felock, Peter J, Flynn, Jessica A, Lai, Ming-Tain, Liang, Yuexia, McGaughey, Georgia, Liu, Meiquing, Miller, Mike, Moyer, Gregory, Munshi, Vandna, Perlow-Poehnelt, Rebecca, Prasad, Sridhar, Reid, John C, Sanchez, Rosa, Torrent, Maricel, Vacca, Joseph P, Wan, Bang-Lin, and Yan, Youwei. Fri . "Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses". United States. doi:10.1021/jm800856c.
@article{osti_1007124,
title = {Discovery of 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): A Potent, Orally Bioavailable HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitor with Improved Potency against Key Mutant Viruses},
author = {Tucker, Thomas J and Sisko, John T and Tynebor, Robert M and Williams, Theresa M and Felock, Peter J and Flynn, Jessica A and Lai, Ming-Tain and Liang, Yuexia and McGaughey, Georgia and Liu, Meiquing and Miller, Mike and Moyer, Gregory and Munshi, Vandna and Perlow-Poehnelt, Rebecca and Prasad, Sridhar and Reid, John C and Sanchez, Rosa and Torrent, Maricel and Vacca, Joseph P and Wan, Bang-Lin and Yan, Youwei},
abstractNote = {Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.},
doi = {10.1021/jm800856c},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (20) ; 10, 2008,
volume = 51,
place = {United States},
year = {2009},
month = {7}
}