Design and synthesis of novel second generation HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs)

MEDI 457

Thomas J Tucker, tom_tucker@merck.com1, Sandeep Saggar1, John T Sisko1, Robert M Tynebor1, Peter J. Felock2, Jessica A Flynn3, Ming-Tain Lai2, Yuexia Liang4, Meiquing Liu2, Mike Miller2, Gregory Moyer3, Vandna Munshi2, Rebecca Perlow-Poehnelt1, Sridhar Prasad5, Rosa Sanchez4, Maricel Torrent1, Joseph P. Vacca1, Theresa M. Williams1, and Bang-LIn Wan1. (1) Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4/WP14-3, Sumneytown Pike, West Point, PA 19486, (2) Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, (3) Vaccines and Biologics Research, Merck Research Laboratories, PO Box 4, West Point, PA 19486, (4) Drug Metabolism Department, Merck Research Laboratories, PO Box 4, West Point, PA 19486, (5) Department of Medicinal Chemistry/Structural Biology, Merck Research Laboratories, P.O. Box 4, Sumneytown Pike, West Point, PA 19486
Since their discovery in the early 1990's, Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active anti-retroviral therapy(HAART). There are currently three commercially available NNRTIs : efavirenz, nevirapine, and delavirdine. The use of efavirenz and nevirapine has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is however a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. The NNRTI program at Merck has been directed towards finding novel NNRTIs that possess high levels of antiviral potency against key clinically observed mutant viruses. 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 spectrum antiviral activity and good pharmacokinetic profiles. This presentation will highlight the design and development of this series of compounds and will describe the progression of these compounds from early lead structures to mature second generation NNRTIs.
 

General Oral Session
9:00 AM-12:20 PM, Thursday, August 23, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007