title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Tucker
authors.forename: John T
authors.initials: JT
authors.lastname: Sisko
authors.forename: Robert M
authors.initials: RM
authors.lastname: Tynebor
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Williams
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Felock
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Flynn
authors.forename: Ming-Tain
authors.initials: MT
authors.lastname: Lai
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Liang
authors.forename: Georgia
authors.initials: G
authors.lastname: McGaughey
authors.forename: Meiquing
authors.initials: M
authors.lastname: Liu
authors.forename: Mike
authors.initials: M
authors.lastname: Miller
authors.forename: Gregory
authors.initials: G
authors.lastname: Moyer
authors.forename: Vandna
authors.initials: V
authors.lastname: Munshi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Perlow-Poehnelt
authors.forename: Sridhar
authors.initials: S
authors.lastname: Prasad
authors.forename: John C
authors.initials: JC
authors.lastname: Reid
authors.forename: Rosa
authors.initials: R
authors.lastname: Sanchez
authors.forename: Maricel
authors.initials: M
authors.lastname: Torrent
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Vacca
authors.forename: Bang-Lin
authors.initials: BL
authors.lastname: Wan
authors.forename: Youwei
authors.initials: Y
authors.lastname: Yan
mesh_terms: 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
chemical_list: 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