Antiviral activity of MK-4965, a novel nonnucleoside reverse transcriptase inhibitor.

Abstract

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 (EC(95)s) of <30 nM in the presence of 10% fetal bovine serum. The antiviral EC(95) 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.

• Authors: Ming-Tain Lai, Vandna Munshi, Sinoeun Touch, Robert M Tynebor, Thomas J Tucker, Philip M McKenna, Theresa M Williams, Daniel J DiStefano, Daria J Hazuda, Michael D Miller
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 53 Issue 6 Pg. 2424-31 (Jun 2009) ISSN: 1098-6596 [Electronic] United States
• PMID: 19289522 (Publication Type: Journal Article)

Chemical References

• 3-(5-((6-amino-1H-pyrazolo(3,4-b)pyridine-3-yl)methoxy)-2-chlorophenoxy)-5-chlorobenzonitrile
• Alkynes
• Anti-HIV Agents
• Benzoxazines
• Cyclopropanes
• Nitriles
• Pyrazoles
• Pyridazines
• Pyridines
• Pyrimidines
• Reverse Transcriptase Inhibitors
• etravirine
• Nevirapine
• reverse transcriptase, Human immunodeficiency virus 1
• HIV Reverse Transcriptase
• efavirenz

Topics

• Alkynes
• Anti-HIV Agents (pharmacology)
• Benzoxazines (pharmacology)
• Cell Line
• Cyclopropanes
• Drug Resistance, Viral
• HIV Reverse Transcriptase (antagonists & inhibitors)
• HIV-1 (drug effects)
• Humans
• Nevirapine (pharmacology)
• Nitriles
• Pyrazoles (pharmacology)
• Pyridazines (pharmacology)
• Pyridines (pharmacology)
• Pyrimidines
• Reverse Transcriptase Inhibitors (pharmacology)