The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutations

Thomas J Tucker; Sandeep Saggar; John T Sisko; Robert M Tynebor; Theresa M Williams; Peter J Felock; Jessica A Flynn; Ming-Tain Lai; Yuexia Liang; Georgia McGaughey; Meiquing Liu; Mike Miller; Gregory Moyer; Vandna Munshi; Rebecca Perlow-Poehnelt; Sridhar Prasad; Rosa Sanchez; Maricel Torrent; Joseph P Vacca; Bang-Lin Wan; Youwei Yan

doi:10.1016/j.bmcl.2008.03.064

The design and synthesis of diaryl ether second generation HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency versus key clinical mutations

Bioorg Med Chem Lett. 2008 May 1;18(9):2959-66. doi: 10.1016/j.bmcl.2008.03.064. Epub 2008 Mar 25.

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, WP14-3, 770 Sumneytown Pike, PO Box 4, West Point, PA 19486-0004, USA. [email protected]

PMID: 18396399
DOI: 10.1016/j.bmcl.2008.03.064

Abstract

Using a combination of traditional Medicinal Chemistry/SAR analysis, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad antiviral activity against a number of key clinical mutations.

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / pharmacology*
Binding Sites
Crystallography, X-Ray
Drug Design*
Drug Resistance, Viral
Ethers / chemistry*
HIV-1 / drug effects*
HIV-1 / enzymology
HIV-1 / genetics
Models, Chemical
Mutation
Nucleosides / chemistry
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship
Virus Replication / drug effects*
Virus Replication / physiology

Substances

Anti-HIV Agents
Ethers
Nucleosides
Reverse Transcriptase Inhibitors

Associated data

PDB/3C6U