Pyridinone derivatives: Specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity

Journal Article · Thu Aug 01 00:00:00 EDT 1991 · Proceedings of the National Academy of Sciences of the United States of America; (United States)

DOI:https://doi.org/10.1073/pnas.88.15.6863· OSTI ID:5604279

Goldman, M E; Nunberg, J H; O'Brien, J A; Quintero, J C; Schleif, W A; Freund, K F; Gaul, S L; Saari, W S; Wai, J S; Hoffman, J M; Anderson, P S; Emini, E A; Stern, A M ^[1]; Hupe, D J ^[2]

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1. Merck Sharp and Dohme Research Labs., West Point, PA (United States)
2. Merck Sharp and Dohme Research Labs., Rahway, NJ (United States)

Derivatives of pyridinones were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevent the spread of HIV-1 infection in cell culture without an appreciable effect on other retroviral or cellular polymerases. 3-{l brace}((4,7-Dimethyl-1,3-benzoxazol-2-yl)methyl)amino{r brace}-5-ethyl-6-methylpyridin-2(1H)-one(L-679,639) and 3-{l brace}((4,7-dichloro-1,3-benzoxazol-2-yl)methyl)amino{r brace}-5-ethyl-6-methylpyridin-2(1H)-one (L-697,661), two compounds within this series, had HIV-1 RT IC{sub 50} values in the range of 20-800 nM, depending upon the template-primer used. The most potent inhibition was obtained with rC{center dot}dG, reversible slow-binding noncompetitive inhibition was observed. ({sup 3}H)L-697,639 bound preferentially to enzyme-template-primer complexes. This binding was magnesium-dependent and saturable with a stoichiometry of 1 mol of ({sup 3}H)L-697,639 per mol of RT heterodimer. Synergism between 3{prime}-azido-3{prime}-deoxythymidine or dideoxyinosine and either of these compounds was also demonstrated in cell culture. Based upon their specificity for HIV-1 RT activity, template-primer dependence on potency and ability to displace ({sup 3}H)L-697,639; a tetrahydroimidazo(4,5,1-jk)(1,4)-benzodiazepin-2(1H)-thione derivative R82150 and the dipyridodiazepinone BI-RG-587 appear to inhibit RT activity by the same mechanism as the pyridinones.

• OSTI ID: 5604279
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (United States), Vol. 88:15; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
DNA POLYMERASES
ENZYME ACTIVITY
ENZYME INHIBITORS
BIOCHEMICAL REACTION KINETICS
PYRIDINES
DERIVATIZATION
AIDS VIRUS
ANTI-INFECTIVE AGENTS
IMIDAZOLES
STOICHIOMETRY
TRITIUM COMPOUNDS
AZINES
AZOLES
CHEMICAL REACTIONS
DRUGS
ENZYMES
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
KINETICS
MICROORGANISMS
NUCLEOTIDYLTRANSFERASES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PARASITES
PHOSPHORUS-GROUP TRANSFERASES
POLYMERASES
PROTEINS
REACTION KINETICS
TRANSFERASES
VIRUSES
550200* - Biochemistry