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Antimicrobial Agents and Chemotherapy, October 2005, p. 4046-4051, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4046-4051.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Antiviral Activity of GW678248, a Novel Benzophenone Nonnucleoside Reverse Transcriptase Inhibitor

Robert G. Ferris,1 Richard J. Hazen,1 Grace B. Roberts,2 Marty H. St. Clair,3 Joseph H. Chan,4,{dagger} Karen R. Romines,5 George A. Freeman,4 Jeffrey H. Tidwell,4 Lee T. Schaller,4 Jill R. Cowan,4 Steven A. Short,6 Kurt L. Weaver,6 Dean W. Selleseth,1 Kelly R. Moniri,1 and Lawrence R. Boone1*

Departments of Virology,1 Biochemistry and Analytical Pharmacology,2 Clinical Virology,3 Medicinal Chemistry,4 Viral Diseases,5 Metabolic and Viral Diseases Center of Excellence in Drug Discovery and Department of Gene Expression and Protein Bichemistry, Discovery Research, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 277096

Received 10 March 2005/ Returned for modification 12 May 2005/ Accepted 28 July 2005

The compound GW678248 is a novel benzophenone nonnucleoside reverse transcriptase inhibitor (NNRTI). Preclinical assessment of GW678248 indicates that this compound potently inhibits wild-type (WT) and mutant human immunodeficiency virus type 1 (HIV-1) reverse transcriptase in biochemical assays, with 50% inhibitory concentrations (IC50s) between 0.8 and 6.8 nM. In HeLa CD4 MAGI cell culture virus replication assays, GW678248 has an IC50 of ≤21 nM against HIV-1 isogenic strains with single or double mutations known to be associated with NNRTI resistance, including L100I, K101E, K103N, V106A/I/M, V108I, E138K, Y181C, Y188C, Y188L, G190A/E, P225H, and P236L and various combinations. An IC50 of 86 nM was obtained with a mutant virus having V106I, E138K, and P236L mutations that resulted from serial passage of WT virus in the presence of GW678248. The presence of 45 mg/ml human serum albumin plus 1 mg/ml {alpha}-1 acid glycoprotein increased the IC50 approximately sevenfold. Cytotoxicity studies with GW678248 indicate that the 50% cytotoxicity concentration is greater than the level of compound solubility and provides a selectivity index of >2,500-fold for WT, Y181C, or K103N HIV-1. This compound exhibits excellent preclinical antiviral properties and, as a prodrug designated GW695634, is being developed as a new generation of NNRTI for the treatment of HIV-1 in combination with other antiretroviral agents.

* Corresponding author. Mailing address: Department of Virology, GlaxoSmithKline, 5 Moore Dr., P.O. Box 13398, Research Triangle Park, NC 27709. Phone: (919) 483-9088. Fax: (919) 315-5243. E-mail: larry.r.boone{at}gsk.com.

{dagger} Present address: Discovery Research Kinase Chemistry, GlaxoSmithKline K.K., Ibaraki, Japan.

Antimicrobial Agents and Chemotherapy, October 2005, p. 4046-4051, Vol. 49, No. 10
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.10.4046-4051.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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