Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Raheem, Izzat T.; Walji, Abbas M.; Klein, Daniel; Sanders, John M.; Powell, David A.; Abeywickrema, Pravien; Barbe, Guillaume; Bennet, Amrith; Clas, Sophie−Dorothee; Dubost, David; Embrey, Mark; Grobler, Jay; Hafey, Michael J.; Hartingh, Timothy J.; Hazuda, Daria J.; Miller, Michael D.; Moore, Keith P.; Pajkovic, Natasa; Patel, Sangita; Rada, Vanessa; Rearden, Paul; Schreier, John D.; Sisko, John; Steele, Thomas G.; Truchon, Jean-François; Wai, John; Xu, Min; Coleman, Paul J.

doi:10.1021/acs.jmedchem.5b01037

Title: Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Full Record
Other Related Research

Abstract

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.

Authors:: Raheem, Izzat T.; Walji, Abbas M.; Klein, Daniel; Sanders, John M.; Powell, David A.; Abeywickrema, Pravien; Barbe, Guillaume; Bennet, Amrith; Clas, Sophie−Dorothee; Dubost, David; Embrey, Mark; Grobler, Jay; Hafey, Michael J.; Hartingh, Timothy J.; Hazuda, Daria J.; Miller, Michael D.; Moore, Keith P.; Pajkovic, Natasa; Patel, Sangita; Rada, Vanessa more »« less

Publication Date:: Thu Oct 22 00:00:00 EDT 2015

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: INDUSTRY

OSTI Identifier:: 1404975

Resource Type:: Journal Article

Journal Name:: Journal of Medicinal Chemistry

Additional Journal Information:: Journal Volume: 58; Journal Issue: 20; Journal ID: ISSN 0022-2623

Publisher:: American Chemical Society (ACS)

Country of Publication:: United States

Language:: ENGLISH

Subject:: 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats


                    Raheem, Izzat T., Walji, Abbas M., Klein, Daniel, Sanders, John M., Powell, David A., Abeywickrema, Pravien, Barbe, Guillaume, Bennet, Amrith, Clas, Sophie−Dorothee, Dubost, David, Embrey, Mark, Grobler, Jay, Hafey, Michael J., Hartingh, Timothy J., Hazuda, Daria J., Miller, Michael D., Moore, Keith P., Pajkovic, Natasa, Patel, Sangita, Rada, Vanessa, Rearden, Paul, Schreier, John D., Sisko, John, Steele, Thomas G., Truchon, Jean-François, Wai, John, Xu, Min, and Coleman, Paul J. Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.  United States: N. p., 2015. 
        Web.  doi:10.1021/acs.jmedchem.5b01037.

Copy to clipboard


                    Raheem, Izzat T., Walji, Abbas M., Klein, Daniel, Sanders, John M., Powell, David A., Abeywickrema, Pravien, Barbe, Guillaume, Bennet, Amrith, Clas, Sophie−Dorothee, Dubost, David, Embrey, Mark, Grobler, Jay, Hafey, Michael J., Hartingh, Timothy J., Hazuda, Daria J., Miller, Michael D., Moore, Keith P., Pajkovic, Natasa, Patel, Sangita, Rada, Vanessa, Rearden, Paul, Schreier, John D., Sisko, John, Steele, Thomas G., Truchon, Jean-François, Wai, John, Xu, Min, & Coleman, Paul J. Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.  United States.  https://doi.org/10.1021/acs.jmedchem.5b01037

Copy to clipboard


                    Raheem, Izzat T., Walji, Abbas M., Klein, Daniel, Sanders, John M., Powell, David A., Abeywickrema, Pravien, Barbe, Guillaume, Bennet, Amrith, Clas, Sophie−Dorothee, Dubost, David, Embrey, Mark, Grobler, Jay, Hafey, Michael J., Hartingh, Timothy J., Hazuda, Daria J., Miller, Michael D., Moore, Keith P., Pajkovic, Natasa, Patel, Sangita, Rada, Vanessa, Rearden, Paul, Schreier, John D., Sisko, John, Steele, Thomas G., Truchon, Jean-François, Wai, John, Xu, Min, and Coleman, Paul J. 2015.  
        "Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors".  United States.  https://doi.org/10.1021/acs.jmedchem.5b01037.

Copy to clipboard


                    
@article{osti_1404975,

  title        = {Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors},

  author       = {Raheem, Izzat T. and Walji, Abbas M. and Klein, Daniel and Sanders, John M. and Powell, David A. and Abeywickrema, Pravien and Barbe, Guillaume and Bennet, Amrith and Clas, Sophie−Dorothee and Dubost, David and Embrey, Mark and Grobler, Jay and Hafey, Michael J. and Hartingh, Timothy J. and Hazuda, Daria J. and Miller, Michael D. and Moore, Keith P. and Pajkovic, Natasa and Patel, Sangita and Rada, Vanessa and Rearden, Paul and Schreier, John D. and Sisko, John and Steele, Thomas G. and Truchon, Jean-François and Wai, John and Xu, Min and Coleman, Paul J.},

  abstractNote = {The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.},

  doi          = {10.1021/acs.jmedchem.5b01037},

  url          = {https://www.osti.gov/biblio/1404975},
  journal      = {Journal of Medicinal Chemistry},

  issn         = {0022-2623},

  number       = 20,

  volume       = 58,

  place        = {United States},

  year         = {Thu Oct 22 00:00:00 EDT 2015},

  month        = {Thu Oct 22 00:00:00 EDT 2015}

}

Copy to clipboard

Journal Article:

https://doi.org/10.1021/acs.jmedchem.5b01037

Other availability

Find in Google Scholar

Search WorldCat to find libraries that may hold this journal

Save / Share:

Export Metadata

Save to My Library

Similar records in OSTI.GOV collections:

Impact of resistance mutations on inhibitor binding to HIV-1 integrase

Journal Article Chen, Qi; Buolamwini, John; Smith, Jeremy; ... - Journal of Chemical Information and Modeling

Here, HIV-1 integrase (IN) is essential for HIV-1 replication, catalyzing two key reaction steps termed 3' processing and strand transfer. Therefore, IN has become an important target for antiviral drug discovery. However, mutants have emerged, such as E92Q/N155H and G140S/Q148H, which confer resistance to raltegravir (RAL), the first IN strand transfer inhibitor (INSTI) approved by the FDA, and to the recently approved elvitegravir (EVG). To gain insights into the molecular mechanisms of ligand binding and drug resistance, we performed molecular dynamics (MD) simulations of homology models of the HIV-1 IN and four relevant mutants complexed with viral DNA and RAL.more »« less
https://doi.org/10.1021/ci400537n
Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection

Journal Article Kudalkar, Shalley; Beloor, Jagadish; Chan, Albert; ... - Molecular Pharmacology

The clinical benefits of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510 µg/ml for compound I and 82.9 µg/ml for compoundmore »« less
https://doi.org/10.1124/mol.116.107755
Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part II. Integrase inhibition

Journal Article Lee-Huang, Sylvia; Huang, Philip; Dawei, Zhang; ... - Biochemical and Biophysical Research Communications

We report molecular modeling and functional confirmation of Ole and HT binding to HIV-1 integrase. Docking simulations identified two binding regions for Ole within the integrase active site. Region I encompasses the conserved D64-D116-E152 motif, while region II involves the flexible loop region formed by amino acid residues 140-149. HT, on the other hand, binds to region II. Both Ole and HT exhibit favorable interactions with important amino acid residues through strong H-bonding and van der Waals contacts, predicting integrase inhibition. To test and confirm modeling predictions, we examined the effect of Ole and HT on HIV-1 integrase activities includingmore »« less
https://doi.org/10.1016/j.bbrc.2007.01.058
Developing a Dynamic Pharmacophore Model for HIV-1 Integrase

Journal Article Carlson, Heather; Masukawa, Keven; Rubins, Kathleen; ... - Journal of Medicinal Chemistry

We present the first receptor-based pharmacophore model for HIV-1 integrase. The development of ''dynamic'' pharmacophore models is a new method that accounts for the inherent flexibility of the active site and aims to reduce the entropic penalties associated with binding a ligand. Furthermore, this new drug discovery method overcomes the limitation of an incomplete crystal structure of the target protein. A molecular dynamics (MD) simulation describes the flexibility of the uncomplexed protein. Many conformational models of the protein are saved from the MD simulations and used in a series of multi-unit search for interacting conformers (MUSIC) simulations. MUSIC is amore »« less
https://doi.org/10.1021/jm990322h
Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H

Journal Article Kankanala, Jayakanth; Kirby, Karen; Huber, Andrew; ... - European Journal of Medicinal Chemistry

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC₅₀ = 0.04 μM) with decent antiviral potency (EC₅₀ = 7.4 μM) and no cytotoxicitymore »« less
Cited by 34
https://doi.org/10.1016/j.ejmech.2017.09.054

Full Text Available

Similar Records