Antiviral activity of MK-4965, a novel nonnucleoside reverse transcriptase inhibitor.
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.
Lai
Ming-Tain
MT
Department of Antiviral Research, Merck Research Laboratories, 770 Sumneytown Pike, West Point, PA 19486, USA. mingtain_lai@merck.com
Munshi
Vandna
V
Touch
Sinoeun
S
Tynebor
Robert M
RM
Tucker
Thomas J
TJ
McKenna
Philip M
PM
Williams
Theresa M
TM
DiStefano
Daniel J
DJ
Hazuda
Daria J
DJ
Miller
Michael D
MD
D000480:Alkynes; D019380:Anti-HIV Agents / Q000494:pharmacology*; D048588:Benzoxazines / Q000494:pharmacology; D002460:Cell Line; D003521:Cyclopropanes; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019829:Nevirapine / Q000494:pharmacology; D009570:Nitriles; D011720:Pyrazoles / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
C532853:3-(5-((6-amino-1H-pyrazolo(3,4-b)pyridine-3-yl)methoxy)-2-chlorophenoxy)-5-chlorobenzonitrile; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D009570:Nitriles; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D019829:Nevirapine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C098320:efavirenz