Discovery of 3-{5-[(6-amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2-chlorophenoxy}-5-chlorobenzonitrile (MK-4965): a potent, orally bioavailable HIV-1 non-nucleoside reverse transcriptase inhibitor with improved potency against key mutant viruses.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standard combination antiviral therapies producing clinical outcomes with efficacy comparable to other antiviral regimens. There is, however, a critical issue with the emergence of clinical resistance, and a need has arisen for novel NNRTIs with a broad spectrum of activity against key HIV-1 RT mutations. Using a combination of traditional medicinal chemistry/SAR analyses, crystallography, and molecular modeling, we have designed and synthesized a series of novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Further refinement of key compounds in this series to optimize physical properties and pharmacokinetics has resulted in the identification of 8e (MK-4965), which has high levels of potency against wild-type and key mutant viruses, excellent oral bioavailability and overall pharmacokinetics, and a clean ancillary profile.
Tucker
Thomas J
TJ
Departments of Medicinal Chemistry and Structural Biology, Merck Research Laboratories, WP14-3, 770 Sumneytown Pike, P.O. Box 4, West Point, PennsylVania 19486-0004, USA. tom_tucker@merck.com
Sisko
John T
JT
Tynebor
Robert M
RM
Williams
Theresa M
TM
Felock
Peter J
PJ
Flynn
Jessica A
JA
Lai
Ming-Tain
MT
Liang
Yuexia
Y
McGaughey
Georgia
G
Liu
Meiquing
M
Miller
Mike
M
Moyer
Gregory
G
Munshi
Vandna
V
Perlow-Poehnelt
Rebecca
R
Prasad
Sridhar
S
Reid
John C
JC
Sanchez
Rosa
R
Torrent
Maricel
M
Vacca
Joseph P
JP
Wan
Bang-Lin
BL
Yan
Youwei
Y
D000284:Administration, Oral; D000818:Animals; D017605:Bromine Compounds / Q000138:chemical synthesis / Q000737:chemistry; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C532853:3-(5-((6-amino-1H-pyrazolo(3,4-b)pyridine-3-yl)methoxy)-2-chlorophenoxy)-5-chlorobenzonitrile; D017605:Bromine Compounds; D009705:Nucleosides; D011720:Pyrazoles; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase