Correlations between factors determining the pharmacokinetics and antiviral activity of HIV-1 non-nucleoside reverse transcriptase inhibitors of the diaryltriazine and diarylpyrimidine classes of compounds

Drugs in R&D
Paul LewiPaul A J Janssen

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

Aug 1, 1988·Journal of Virological Methods·R PauwelsE De Clercq
Feb 17, 1997·Virology·L WangM W Cloyd
Aug 15, 1997·Science·J L Madara
Mar 31, 2000·Trends in Cell Biology·F Niedergang, J P Kraehenbuhl
Apr 20, 2001·Journal of Medicinal Chemistry·H van De WaterbeemdD K Walker
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

❮ Previous
Next ❯

Citations

Feb 19, 2015·Therapeutic Delivery·Anthony S Ham, Robert W Buckheit
Jan 20, 2016·Journal of Medicinal Chemistry·Sergey SergeyevBert U W Maes
Mar 18, 2005·Journal of Medicinal Chemistry·Yulia Volovik FrenkelEddy Arnold

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

CSF & Lymphatic System

This feed focuses on Cerebral Spinal Fluid (CSF) and the lymphatic system. Discover the latest papers using imaging techniques to track CSF outflow into the lymphatic system in animal models.