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Antimicrobial Agents and Chemotherapy, September 2007, p. 3147-3154, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00401-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro Antiviral Activity of the Novel, Tyrosyl-Based Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor Brecanavir (GW640385) in Combination with Other Antiretrovirals and against a Panel of Protease Inhibitor-Resistant HIV{triangledown}

Richard Hazen,1* Robert Harvey,1 Robert Ferris,1 Charles Craig,1 Phillip Yates,1 Philip Griffin,1 John Miller,2 Istvan Kaldor,2 John Ray,2 Vincente Samano,2 Eric Furfine,4,{dagger} Andrew Spaltenstein,2 Michael Hale,5,{ddagger} Roger Tung,5,§ Marty St. Clair,1 Mary Hanlon,3 and Lawrence Boone1

Metabolic and Viral Diseases CEDD, Departments of Virology,1 Medicinal Chemistry,2 Biochemistry & Analytical Pharmacology,3 Molecular Biochemistry, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709,4 Vertex Pharmaceuticals, Cambridge, Massachusetts5

Received 23 March 2007/ Returned for modification 3 May 2007/ Accepted 2 July 2007

Brecanavir, a novel tyrosyl-based arylsulfonamide, high-affinity, human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI), has been evaluated for anti-HIV activity in several in vitro assays. Preclinical assessment of brecanavir indicated that this compound potently inhibited HIV-1 in cell culture assays with 50% effective concentrations (EC50s) of 0.2 to 0.53 nM and was equally active against HIV strains utilizing either the CXCR4 or CCR5 coreceptor, as was found with other PIs. The presence of up to 40% human serum decreased the anti-HIV-1 activity of brecanavir by 5.2-fold, but under these conditions the compound retained single-digit nanomolar EC50s. When brecanavir was tested in combination with nucleoside reverse transcriptase inhibitors, the antiviral activity of brecanavir was synergistic with the effects of stavudine and additive to the effects of zidovudine, tenofovir, dideoxycytidine, didanosine, adefovir, abacavir, lamivudine, and emtricitabine. Brecanavir was synergistic with the nonnucleoside reverse transcriptase inhibitor nevirapine or delavirdine and was additive to the effects of efavirenz. In combination with other PIs, brecanavir was additive to the activities of indinavir, lopinavir, nelfinavir, ritonavir, amprenavir, saquinavir, and atazanavir. Clinical HIV isolates from PI-experienced patients were evaluated for sensitivity to brecanavir and other PIs in a recombinant virus assay. Brecanavir had a <5-fold increase in EC50s against 80% of patient isolates tested and had a greater mean in vitro potency than amprenavir, indinavir, lopinavir, atazanavir, tipranavir, and darunavir. Brecanavir is by a substantial margin the most potent and broadly active antiviral agent among the PIs tested in vitro.

* Corresponding author. Mailing address: Department of Virology, GlaxoSmithKline, 5 Moore Dr., P.O. Box 13398, Research Triangle Park, NC 27709. Phone: (919) 483-9179. Fax: (919) 315-5243. E-mail: richard.j.hazen{at}gsk.com

{triangledown} Published ahead of print on 9 July 2007.

{dagger} Present address: Adnexus Therapeutics, Waltham, MA.

{ddagger} Present address: AstraZeneca Pharmaceuticals, Waltham, MA.

§ Present address: Concert Pharmaceuticals, Lexington, MA.

Antimicrobial Agents and Chemotherapy, September 2007, p. 3147-3154, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00401-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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