2-Pyridinone derivatives: a new class of nonnucleoside, HIV-1-specific reverse transcriptase inhibitors

Saari, W. S.; Hoffman, J. M.; Wai, John S.; Fisher, Thorsten E.; Rooney, C. S.; Smith, Anthony M.; Thomas, Craig; Goldman, Mark E.; O’Brien, Julie A.; Nunberg, Jack H.

doi:10.1021/jm00113a036

Cited by 102 publications

(30 citation statements)

References 4 publications

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“…Measured in HIV-l IIIB-infected MT-4 cells, the IC so reported for EBPU, HEPT and AZT are 0.0049, 6.5 and 0.003 flM, respectively (Baba et al, 1991) and the IC 9s (concentration inhibiting virus multiplication by 95%) for L-696,229 is 0.05-0.1 u.M (Saari et al, 1991). The new pyridinone derivatives described were evaluated using different experimental conditions involving CEM-SS cells infected with HIV-I LA1 (Table 1) and AZT and HEPT were included as references (IC so 0.002 fllVI and 2 flM respectively, values similar to those reported for infected MT4 cells).…”

Section: Discussionmentioning

confidence: 99%

“…These compounds have been called 'non-nucleoside reverse transcriptase inhibitors'. Among these are the HEPT (Tanaka et al, 1991a,b), TIBO (Pauwels et al, 1990;Debyser et al, 1991), nevirapine (Merluzzi et al, 1990;Koup et al, 1991), pyridinone (Hoffman et al, , 1993Saari et al, 1991Saari et al, , 1992Wai et al, 1993), a-APA (Pauwels et al, 1993) and BHAP (Romero et al, 1991(Romero et al, , 1993 derivatives. They specifically inhibit HIV-1 RT by acting non-competitively at an allosteric site (Mellors et al,1991).…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis and Antiviral Activity of New Pyridinone Derivatives

Jourdan

Renault

Fossey

et al. 1997

Antivir Chem Chemother

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Fax: +33 2 31 93 11 88. SummaryA molecular modelling study was carried out in order to compare the structural and electronic properties of the pyridinone L-696,229 and the HEPT derivative EBPU. This comparison led to a hybrid structure, 3-(benzyloxymethyl)-5-ethyl-6-methylpyridin-2-one [18aL which revealed a good structural correlation with the models. A series of 2-[(arylmethyl)oxymethyl]pyridin-2-ones related to [18a] was synthesized and tested for antiviral activity against human immunodeficiency virus type 1 (HIV-1). Compound [18a] and four other derivatives showed anti-HIV-1 activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Antiviral Activity of New Pyridinone Derivatives

Jourdan

Renault

Fossey

et al. 1997

Antivir Chem Chemother

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“…Two different types of anti-RT compounds have received the most attention: nucleoside analogues (Connolly & Hammer, 1992), such as AZT (zidovudinc) (Mitsuya et al, 1985), ddC (zalcitabine) and ddI (didanosine) (Mitsuya & Broder, 1986), and nonnucleoside compounds, such as 9-Cl-TIBO (Pauwels et al, 1990;Kukla et al, 1991;Debyser et al, 1991), HEPT derivatives (Miyasaka et al, 1989), nevirapine (Merluzzi et al, 1990;Hargrave et al, 1991;Hui et al, 1992), BHAP compounds (Romero et al, 1991), pyridinone compounds Saari et al, 1991), quinoline analogues (Althaus et al, 1993a), and phenethylthiazole thiourea (PETT) compounds (Ternansky et al, 1993;Ahgren et al, 1995;Cantrell et al, 1996). However, the clinical utility of many of these compounds has been hampered by toxicity and limited overall clinical efficacy (Sandstrom & Oberg, 1993a,b).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase by Degradation Products of Ceftazidime

Baertschi

Kuhfeld

et al. 1997

Antivir Chem Chemother

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SummaryPrevious work by Hafkemeyer et a/. (1991) [Nucleic Acids Research 19: [4059][4060][4061][4062][4063][4064][4065] indicated that a degradation product of ceftazidime, termed HP 0.35, was active against the RNase H activity of human immunodeficiency virus type 1 (HIV-1) and feline immunodeficiency virus (FIV) reverse transcriptase (RT) in vitro. Attempting to repeat these results, we isolated HP 0.35 from an aqueous degradation of ceftazidime and, after careful purification, we found HP 0.35 to be essentially inactive against both the polymerase and RNase H domains of HIV-1 RT (IC 50 of>100 I1g mL-1). During the investigation we discovered that polymeric degradation products of ceftazidime inhibited both the polymerase and, to a greater extent, the RNase H activities of HIV-1 RT in vitro (IC 50 approximately 0.1 and 0.01 I1g mt', respectively). Subjecting HP 0.35 to conditions under which it could polymerize induced inhibitory activity similar to that of the polymeric ceftazidime degradation products. It is proposed that the previously reported activity of HP 0.35 may have resulted from the presence of low levels of polymeric material either from incomplete purification or from polymerization of HP 0.35 during storage or in vitro testing.

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“…These compounds also inhibited human immunodeficiency virus type 2 (HIV-2), but did not inhibit viral RT (Goudgaon and Schinazi, 1991). This class of acyclic pyrimidines containing 6-phenylselenenyl group is important to develop, not only because of their activity against various retroviruses, but also because their spectrum of activity is different from 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPl) and TISO-like compounds (Merluzzi et al, 1990;Pauwels et al, 1990;Goldman et aI., 1991;Saari et al, 1991;Tanaka et al, 1991aTanaka et al, , 1991b. Substitution of a primary hydroxyl group for a hydrogen in the acyclic side chain may enhance the antiviral activity.…”

Section: Introductionmentioning

confidence: 99%