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Antimicrobial Agents and Chemotherapy, June 2009, p. 2424-2431, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01559-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antiviral Activity of MK-4965, a Novel Nonnucleoside Reverse Transcriptase Inhibitor{triangledown}

Ming-Tain Lai,1* Vandna Munshi,1 Sinoeun Touch,2 Robert M. Tynebor,3 Thomas J. Tucker,3 Philip M. McKenna,1 Theresa M. Williams,3 Daniel J. DiStefano,2 Daria J. Hazuda,1 and Michael D. Miller1

Department of Antiviral Research,1 Department of Vaccine Basic Research,2 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 194863

Received 23 November 2008/ Returned for modification 25 January 2009/ Accepted 7 March 2009

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are the mainstays of therapy for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, the effectiveness of NNRTIs can be hampered by the development of resistance mutations which confer cross-resistance to drugs in the same class. Extensive efforts have been made to identify new NNRTIs that can suppress the replication of the prevalent NNRTI-resistant viruses. MK-4965 is a novel NNRTI that possesses both diaryl ether and indazole moieties. The compound displays potency at subnanomolar concentrations against wild-type (WT), K103N, and Y181C reverse transcriptase (RT) in biochemical assays. MK-4965 is also highly potent against the WT virus and two most prevalent NNRTI-resistant viruses (viruses that harbor the K103N or the Y181C mutation), against which it had 95% effective concentrations (EC95s) of <30 nM in the presence of 10% fetal bovine serum. The antiviral EC95 of MK-4965 was reduced approximately four- to sixfold when it was tested in 50% human serum. Moreover, MK-4965 was evaluated with a panel of 15 viruses with NNRTI resistance-associated mutations and showed a superior mutant profile to that of efavirenz but not to that of etravirine. MK-4965 was similarly effective against various HIV-1 subtypes and viruses containing nucleoside reverse transcriptase inhibitor or protease inhibitor resistance-conferring mutations. A two-drug combination study showed that the antiviral activity of MK-4965 was nonantagonistic with each of the 18 FDA-licensed drugs tested vice versa in the present study. Taken together, these in vitro data show that MK-4965 possesses the desired properties for further development as a new NNRTI for the treatment of HIV-1 infection.

* Corresponding author. Mailing address: Department of Antiviral Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486. Phone: (215) 652-5038. Fax: (215) 993-6842. E-mail: mingtain_lai{at}merck.com

{triangledown} Published ahead of print on 16 March 2009.

Antimicrobial Agents and Chemotherapy, June 2009, p. 2424-2431, Vol. 53, No. 6
0066-4804/09/$08.00+0     doi:10.1128/AAC.01559-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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