Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 4. 3-[2-(Benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one and analogues.
A new series of potent specific 2-pyridinone reverse transcriptase (RT) inhibitors was developed based on the preliminary development lead 3-[(phthalmido)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (3), a non-nucleoside derivative which exhibited weak antiviral activity in cell culture against HIV-1 strain IIIB. One compound, 3-[(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (9,L-696,229), which was a highly selective antagonist of the RT enzyme (IC50 = 23 nM) and which inhibited the spread of HIV-1 IIIB infection by > 95% in MT4 human T-lymphoid cell culture (CIC95 = 50-100 nM), was selected for clinical evaluation as an antiviral agent.
Hoffman
J M
JM
Department of Medicinal Chemistry, Merck Reserch Laboratories, West Point, Pennsylvania 19486-0004.
Smith
A M
AM
Rooney
C S
CS
Fisher
T E
TE
Wai
J S
JS
Thomas
C M
CM
Bamberger
D L
DL
Barnes
J L
JL
Williams
T M
TM
Jones
J H
JH
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002478:Cells, Cultured; D004341:Drug Evaluation; D054303:HIV Reverse Transcriptase; D006801:Humans; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D001583:Benzoxazoles; D001798:Blood Proteins; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; C076250:L 696229; D054303:HIV Reverse Transcriptase