The treatment of chronic hepatitis B: Focus on adefovir-like antivirals

Tillmann, Hans L.

doi:10.2147/tcrm.s1965

Cited by 5 publications

(3 citation statements)

References 33 publications

(35 reference statements)

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“…Adefovir is FDA approved for treatment of hepatitis B infections, while tenofovir is FDA approved for treatment of HIV and hepatitis B infections 73-76. Analogues of current antiviral compounds are important for addressing the spread of viral resistance.…”

Section: Results and Disscussionmentioning

confidence: 99%

“…(9 H -Purin-9-yl)alcohols are key substructures of the commercial antivirals adefovir and tenofovir, which are adenine analogues (Figure ). Adefovir is FDA approved for treatment of hepatitis B infections, while tenofovir is FDA approved for treatment of HIV and hepatitis B infections. − Analogues of current antiviral compounds are important for addressing the spread of viral resistance. Thus, we sought to illustrate how chiral N -allylated adenine derivatives could be converted to α-adeninyl alcohols and β-adeninyl alcohols, which are optically active α-substituted analogues of the antiretrovirals adefovir and tenofovir (Scheme ).…”

Section: Results and Disscussionmentioning

confidence: 99%

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Regio- and Enantioselective N-Allylations of Imidazole, Benzimidazole, and Purine Heterocycles Catalyzed by Single-Component Metallacyclic Iridium Complexes

2009

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Highly regio-and enantioselective iridium-catalyzed N-allylations of benzimidazoles, imidazoles, and purines have been developed. N-Allylated benzimidazoles and imidazoles were isolated in high yields (up to 97%) with high branched-to-linear selectivity (up to 99:1) and enantioselectivity (up to 98% ee) from the reactions of benzimidazole and imidazole nucleophiles with unsymmetrical allylic carbonates in the presence of single component, ethylene-bound, metallacyclic iridium catalysts. NAllylated purines were also obtained in high yields (up to 91%) with high N9:N7 selectivity (up to 96:4), high branched-to-linear selectivity (98:2), and high enantioselectivity (up to 98% ee) under similar conditions. The reactions encompass a range of benzimidazole, imidazole, and purine nucleophiles, as well as a variety of unsymmetrical aryl, heteroaryl, and aliphatic allylic carbonates. Competition experiments between common amine nucleophiles and the heterocyclic nitrogen nucleophiles studied in this work illustrate the effect of nucleophile pK a on the rate of iridiumcatalyzed N-allylation reactions. Kinetic studies on the allylation of benzimidazole catalyzed by metallacyclic iridium-phosphoramidite complexes, in combination with studies on the deactivation of these catalysts in the presence of heterocyclic nucleophiles, provide insight into the effects of the structure of the phosphoramidite ligands on the stability of the metallacyclic catalysts. The data obtained from these studies has led to the development of N-allylations of benzimidazoles and imidazoles in the absence of an exogenous base.

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Section: Results and Disscussionmentioning

confidence: 99%

Section: Results and Disscussionmentioning

confidence: 99%

Regio- and Enantioselective N-Allylations of Imidazole, Benzimidazole, and Purine Heterocycles Catalyzed by Single-Component Metallacyclic Iridium Complexes

2009

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“…There was no association between substitution of either valine or isoleucine and outcome when no other treatment option was available [Enomoto et al, 2007]. Likewise, there is no evidence for a role of rtM204I versus rtM204V concerning subsequent patient's clinical response when treated with adefovir or tenofovir [Tillmann, 2008]. This aspect, however, has changed with the availability of two other drugs known to select mutations in the YMDD motif, entecavir, and telbivudine.…”

Section: Introductionmentioning

confidence: 99%

Mutation pattern of lamivudine resistance in relation to hepatitis B genotypes: Hepatitis B genotypes differ in their lamivudine resistance associated mutation pattern

Damerow

Yuen

Walker

et al. 2010

Journal of Medical Virology

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Little is known about differences between individual hepatitis B genotypes and mutation patterns associated with lamivudine resistance. This study analyses the lamivudine‐associated mutation pattern in relation to the four major HBV genotypes A–D. The PubMed database was screened for keywords “HBV OR Hepatitis B,” “YMDD,” “genotype,” and “lamivudine”; all identified publications published till June 2009 were analyzed for differences in mutation pattern. To confirm the literature‐based findings the databases of two reference laboratories in Tübingen (Germany), and Melbourne (Australia) were analyzed. Twenty‐nine studies were identified reporting 827 patients with known hepatitis B genotype who underwent lamivudine treatment and developed resistance mutations. The literature data revealed that genotype A favors the rtM204V mutation unlike the other major genotypes (P < 0.001), which corresponds to a significant difference in the mutation pattern of genotypes endemic in Asian countries and those found in the rest of the world. These significant findings of the literature‐review could be reproduced in the analysis of the databases from Tübingen and Melbourne. Furthermore, the rtL180M mutation is significantly connected to the rtM204V mutation in genotypes A, B, and C, respectively. It is concluded that there is proof that HBV genotypes differ in their mutation pattern of lamivudine resistance. Future studies will need to evaluate whether this will translate into genotype‐specific differences in resistance emergence on either entecavir or telbivudine as these antivirals differ in their mutation profile, rtM204V for entecavir and rtM204I for telbivudine. J. Med. Virol. 82:1850–1858, 2010. © 2010 Wiley‐Liss, Inc.

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