Fused heterocyclic amido compounds as anti-hepatitis C virus agents

Aoyama, Hiroshi; Sugita, Kazuyuki; Nakamura, Masahiko; Aoyama, Atsushi; Salim, Mohammed T.A.; Okamoto, Masato; Baba, Masanori; Hashimoto, Yuichi

doi:10.1016/j.bmc.2011.03.002

Cited by 22 publications

(13 citation statements)

References 29 publications

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“…For this work, compounds 1 – 3 , 7 – 42 and 44 were prepared as described previously [ 9 , 10 , 15 ]. PR-antagonistic activity was evaluated by assay of PR-regulated alkaline phosphatase activity in human breast cancer cell line T47D [ 10 , 16 ] while RORα, RORβ and RORγ inverse agonistic activities, and LXRα, LXRβ, AR and GR antagonistic activities were evaluated by reporter gene assay in HEK293 cell line [ 9 , 10 ].…”

Section: Resultsmentioning

confidence: 99%

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

Nishiyama

Fujii

Makishima

et al. 2018

IJMS

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Background: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for clinical use. We anticipated that efficient lead finding and enhancement of activity toward nuclear receptors recognizing endogenous steroidal ligands might be achieved by exhaustive evaluation of a steroid surrogate library coupled with examination of structure-activity relationships (SAR). Method: We evaluated our library of RORs (retinoic acid receptor-related orphan receptors) inverse agonists and/or PR (progesterone receptor) antagonists based on the phenanthridinone skeleton for antagonistic activities toward liver X receptors (LXRs), androgen receptor (AR) and glucocorticoid receptor (GR) and examined their SAR. Results: Potent LXRβ, AR, and GR antagonists were identified. SAR studies led to a potent AR antagonist (IC50: 0.059 μM). Conclusions: Our approach proved effective for efficient lead finding, activity enhancement and preliminary control of selectivity over other receptors. The phenanthridinone skeleton appears to be a promising steroid surrogate.

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Section: Resultsmentioning

confidence: 99%

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

Nishiyama

Fujii

Makishima

et al. 2018

IJMS

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“…HA-719 was synthesized by Dr. Hashimoto and his colleagues, according to the method previously described. 15 The NS3 protease inhibitor telaprevir (TLV), the NS5A inhibitor DCV, and the non-nucleoside NS5B polymerase inhibitor VX-222 were purchased from AdooQ BioScience (Irvine, CA). [16][17][18] All compounds were dissolved in dimethyl sulfoxide at a concentration of 20 mM and stored at À20 C until use.…”

Section: Methods Compoundsmentioning

confidence: 99%

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Baba¹

2016

Preprint

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Background: The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719. Methods: To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719. After several passages, total RNA was extracted from the growing cells, and Huh-7 cells were transfected with the extracted RNA. Limiting dilution of the transfected cells was performed to obtain an HA-719-resistant clone. Results: The 50% effective concentration (EC 50) of HA-719 for hepatitis C virus replication was 0.058 AE 0.012 mM in LucNeo#2 cells. The replicon cells capable of growing in the presence of G418 and 3 mM HA-719 were obtained after 18 passages (72 days). The HA-719-resistant clone LucNeo719R showed 98.3-fold resistant to the compound (EC 50 ¼ 5.66 AE 0.92 mM), but the clone had no cross-resistance to telaprevir (NS3 inhibitor), daclatasvir (NS5A inhibitor), and VX-222 (NS5B inhibitor). The sequence analysis for the wild-type and LucNeo719R identified 3, 2 and 7 mutations in NS3/4 A, NS4B, and NS5A, respectively, but no mutations in NS5B. Conclusion: None of the amino acid mutations in the resistant clone corresponds to those reported to confer drugresistance to current anti-hepatitis C virus agents, suggesting that the target of HA-719 for hepatitis C virus inhibition differs from those of the existing agents.

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“…A regioselective C-3 phenylation of 1-methylquinolin-4(1H)one was reported by Choi et al (Scheme 2) [86], and Hartwig's group presented the regioselective arylation of a number of mono-and disubstituted arenes using synergistic silver and palladium catalysis [87]. Direct arylation has been a tool for the construction of several natural products, polycyclic aromatic hydrocarbons (PAHs) and other chemically relevant compounds [88][89][90]. Indeed, the structure of several biologically relevant lactones prepared by direct arylation, including Defucogilocarcins M and E [91,92], and intermediates for the syntheses of Dioncophylline A and Mastigophorene B [93][94][95], are shown in Figure 2.…”

Section: Introductionmentioning

confidence: 98%

Direct Arylation in the Presence of Palladium Pincer Complexes

et al. 2021

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Direct arylation is an atom-economical alternative to more established procedures such as Stille, Suzuki or Negishi arylation reactions. In comparison with other palladium sources and ligands, the use of palladium pincer complexes as catalysts or pre-catalysts for direct arylation has resulted in improved efficiency, higher reaction yields, and advantageous reaction conditions. In addition to a revision of the literature concerning intra- and intermolecular direct arylation reactions performed in the presence of palladium pincer complexes, the role of these remarkably active catalysts will also be discussed.

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Fused heterocyclic amido compounds as anti-hepatitis C virus agents

Cited by 22 publications

References 29 publications

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

Isolation and characterization of hepatitis C virus resistant to a novel phenanthridinone derivative

Direct Arylation in the Presence of Palladium Pincer Complexes

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