Diphenyl Ether Non-Nucleoside Reverse Transcriptase Inhibitors with Excellent Potency Against Resistant Mutant Viruses and Promising Pharmacokinetic Properties

✍ Scribed by Zachary K. Sweeney; Joshua J. Kennedy-Smith; Jeffrey Wu; Nidhi Arora; J. Roland Billedeau; James P. Davidson; Jennifer Fretland; Julie Q. Hang; Gabrielle M. Heilek; Seth F. Harris; Donald Hirschfeld; Petra Inbar; Hassan Javanbakht; Jesper A. Jernelius; Qingwu Jin; Yu Li; Weiling Liang; Ralf Roetz; Keshab Sarma; Mark Smith; Dimitrio Stefanidis; Guoping Su; Judy M. Suh; Armando G. Villaseñor; Michael Welch; Fang-Jie Zhang; Klaus Klumpp

• Book ID: 102805277
• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 521 KB
• Volume: 4
• Category: Article
• ISSN: 1860-7179
• DOI: 10.1002/cmdc.200800262

✦ Synopsis

Abstract

Non‐nucleoside reverse transcriptase inhibitors (NNRTIs) are part of the preferred treatment regimens for individuals infected with HIV. These NNRTI‐based regimens are efficacious, but the most popular NNRTIs have a low genetic barrier to resistance and have been associated with adverse events. There is therefore still a need for efficacious antiviral medicines that facilitate patient adherence and allow durable suppression of viral replication. As part of an extensive program targeted toward the discovery of NNRTIs that have favorable pharmacokinetic properties, good potency against NNRTI‐resistant viruses, and a high genetic barrier to drug resistance, we focused on the optimization of a series of diaryl ether NNRTIs. In the course of this effort, we employed molecular modeling to design a new set of NNRTIs that that are active against wild‐type HIV and key NNRTI‐resistant mutant viruses. The structure–activity relationships observed in this series of compounds provide insight into the structural features required for NNRTIs that inhibit the replication of a wide range of mutant viruses. Selected compounds have promising pharmacokinetic profiles.