Abstract
To investigate the important factors that determine the bioavailability and the antiviral activity of the diaryltriazine (DATA) and diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 in animal species and humans using cell-based assays, physicochemical and computed parameters. This naturalistic study included 15 parameters ranging from molecular mechanics calculations to phase I clinical trials. The calculated parameters were solvent-accessible surface area (SASA), polar surface area and Gibbs free energy of solvation. Physicochemical parameters comprised lipophilicity (octanol/water partition coefficient [cLogP]), ionisation constant (pKa), solubility and aggregate radius. Cell-based assays included human colonic adenocarcinoma cell (Caco-2) permeability (transepithelial transport), drug metabolism and antiviral activity (negative logarithm of the molar effective concentration inhibiting viral replication by 50% [pEC50]). Exposure was tested in rats, dogs and human volunteers. Of the 15 parameters, eight correlated consistently among one another. Exposure (area under the plasma concentration-time curve [AUC]) in humans correlated positively with that in rats (r = 1.00), with transepitheli...Continue Reading
References
Jun 26, 1992·Science·L A KohlstaedtT A Steitz
Feb 1, 1990·Nature·R PauwelsJ Heykants
Dec 16, 1991·FEBS Letters·M SkouriR Giegé
Aug 1, 1988·Journal of Virological Methods·R PauwelsE De Clercq
Aug 19, 1983·Science·M L Connolly
Apr 15, 1995·Structure·J DingK Andries
May 1, 1995·Nature Structural Biology·J DingE Arnold
Aug 1, 1994·AIDS·C TamaletP de Micco
Mar 1, 1997·Pharmaceutical Research·A T Florence
Feb 17, 1997·Virology·L WangM W Cloyd
Aug 15, 1997·Science·J L Madara
Mar 21, 1998·Nature Medicine·G PantaleoA S Fauci
Jun 26, 1999·Seminars in Immunology·D Kaiserlian, N Etchart
Mar 31, 2000·Trends in Cell Biology·F Niedergang, J P Kraehenbuhl
Jun 6, 2000·Advanced Drug Delivery Reviews·P YehP L Smith
Apr 20, 2001·Journal of Medicinal Chemistry·H van De WaterbeemdD K Walker
May 18, 2001·Journal of Pharmaceutical Sciences·Y H ZhaoD Boutina
Aug 8, 2001·Advanced Drug Delivery Reviews·C J Porter, W N Charman
Aug 31, 2001·Bioorganic & Medicinal Chemistry Letters·D W LudoviciP A Janssen
Aug 31, 2001·Bioorganic & Medicinal Chemistry Letters·D W LudoviciP A Janssen
Aug 31, 2001·Bioorganic & Medicinal Chemistry Letters·D W LudoviciP A Janssen
Mar 20, 2002·Current Topics in Medicinal Chemistry·H BohetsK Lavrijsen
Apr 5, 2002·Journal of Medicinal Chemistry·Susan L McGovernBrian K Shoichet
Sep 19, 2003·Journal of Computer-aided Molecular Design·Paul J LewiPaul J Lewis
Sep 19, 2003·Journal of Medicinal Chemistry·Susan L McGovernBrian K Shoichet
Oct 3, 2003·Journal of Medicinal Chemistry·James SeidlerBrian K Shoichet
Apr 30, 2004·Journal of Medicinal Chemistry·Kalyan DasEddy Arnold
Citations
Nov 11, 2011·Pharmaceutical Research·José das NevesBruno Sarmento
Feb 19, 2015·Therapeutic Delivery·Anthony S Ham, Robert W Buckheit
Dec 8, 2010·Chemical Biology & Drug Design·Zeng LiHai-Feng Chen
Sep 24, 2013·PloS One·Anthony S HamRobert W Buckheit
Sep 11, 2020·ChemMedChem·Javier García-MarínDiego Rodríguez-Puyol
Sep 11, 2009·Journal of Medicinal Chemistry·Yulia Volovik FrenkelEddy Arnold
Jan 20, 2016·Journal of Medicinal Chemistry·Sergey SergeyevBert U W Maes
Mar 18, 2005·Journal of Medicinal Chemistry·Paul A J JanssenPaul Stoffels
Mar 18, 2005·Journal of Medicinal Chemistry·Yulia Volovik FrenkelEddy Arnold