Discovery of MK-8970: an acetal carbonate prodrug of raltegravir with enhanced colonic absorption.

Abstract

Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.

• Authors: Abbas M Walji, Rosa I Sanchez, Sophie-Dorothee Clas, Rebecca Nofsinger, Manuel de Lera Ruiz, Jing Li, Amrithraj Bennet, Christopher John, David Jonathan Bennett, John M Sanders, Christina N Di Marco, Somang Hope Kim, Jaume Balsells, Scott S Ceglia, Qun Dang, Kimberly Manser, Becky Nissley, John S Wai, Michael Hafey, Junying Wang, Gene Chessen, Allen Templeton, John Higgins, Ronald Smith, Yunhui Wu, Jay Grobler, Paul J Coleman
• Journal: ChemMedChem (ChemMedChem) Vol. 10 Issue 2 Pg. 245-52 (Feb 2015) ISSN: 1860-7187 [Electronic] Germany
• PMID: 25469982 (Publication Type: Journal Article)
• Copyright: © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Acetals
• Carbonates
• HIV Integrase Inhibitors
• Oxadiazoles
• Prodrugs
• Pyrimidinones
• Pyrrolidinones
• ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl)carbonate
• Raltegravir Potassium
• HIV Integrase

Topics

• Acetals (chemistry)
• Animals
• Area Under Curve
• Carbonates (chemistry)
• Dogs
• Drug Evaluation, Preclinical
• HIV Integrase (chemistry, metabolism)
• HIV Integrase Inhibitors (chemical synthesis, chemistry, pharmacokinetics)
• HIV-1 (enzymology)
• Half-Life
• Hepatocytes (metabolism)
• Humans
• Intestinal Mucosa (metabolism)
• Male
• Oxadiazoles (chemical synthesis, chemistry, pharmacokinetics)
• Prodrugs (chemical synthesis, chemistry, pharmacokinetics)
• Pyrimidinones (chemical synthesis, chemistry, pharmacokinetics)
• Pyrrolidinones (chemistry)
• ROC Curve
• Raltegravir Potassium
• Rats
• Rats, Wistar
• Structure-Activity Relationship