5 research outputs found
Методичні вказівки для проведення практичних занять і організації самостійної роботи з навчальної дисципліни «Управління нерухомим майном» (для студентів 4 курсу денної і заочної форм навчання напряму підготовки 6.080101 – Геодезія, картографія та землеустрій).
Table S2. Week-4 simeprevir pharmacokinetic parameters after administration in (a) Panels 1â3 and (b) Panel 4. (DOCX 15 kb
Additional file 1: of Virology analysis in HCV genotype 1-infected patients treated with the combination of simeprevir and TMC647055/ritonavir, with and without ribavirin, and JNJ-56914845
Study design. HCV NS3/4A, NS5B and NS5A sequence analysis. (DOCX 32Â kb
Discovery of 1‑((2<i>R</i>,4a<i>R</i>,6<i>R</i>,7<i>R</i>,7a<i>R</i>)‑2-Isopropoxy-2-oxidodihydro‑4<i>H</i>,6<i>H</i>‑spiro[furo[3,2‑<i>d</i>][1,3,2]dioxaphosphinine-7,2′-oxetan]-6-yl)pyrimidine-2,4(1<i>H</i>,3<i>H</i>)‑dione (JNJ-54257099), a 3′-5′-Cyclic Phosphate Ester Prodrug of 2′-Deoxy-2′-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition
JNJ-54257099 (<b>9</b>) is
a novel cyclic phosphate ester
derivative that belongs to the class of 2′-deoxy-2′-spirooxetane
uridine nucleotide prodrugs which are known as inhibitors of the HCV
NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype
(GT) 1b replicon-containing cell line <b>9</b> is devoid of
any anti-HCV activity, an observation attributable to inefficient
prodrug metabolism which was found to be CYP3A4-dependent. In contrast,
in vitro incubation of <b>9</b> in primary human hepatocytes
as well as pharmacokinetic evaluation thereof in different preclinical
species reveals the formation of substantial levels of 2′-deoxy-2′-spirooxetane
uridine triphosphate (<b>8</b>), a potent inhibitor of the HCV
NS5B polymerase. Overall, it was found that <b>9</b> displays
a superior profile compared to its phosphoramidate prodrug analogues
(e.g., <b>4</b>) described previously. Of particular interest
is the in vivo dose dependent reduction of HCV RNA observed in HCV
infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days
of oral administration of <b>9</b>
Nucleotide Prodrugs of 2′-Deoxy-2′-spirooxetane Ribonucleosides as Novel Inhibitors of the HCV NS5B Polymerase
The limited efficacy, in particular
against the genotype 1 virus,
as well as the variety of side effects associated with the current
therapy for hepatitis C virus (HCV) infection necessitates more efficacious
drugs. We found that phosphoramidate prodrugs of 2′-deoxy-2′-spirooxetane
ribonucleosides form a novel class of HCV NS5B RNA-dependent RNA polymerase
inhibitors, displaying EC<sub>50</sub> values ranging from 0.2 to
>98 μM, measured in the Huh7-replicon cell line, with no
apparent
cytotoxicity (CC<sub>50</sub> > 98.4 μM). Confirming recent
findings, the 2′-spirooxetane moiety was identified as a novel
structural motif in the field of anti-HCV nucleosides. A convenient
synthesis was developed that enabled the synthesis of a broad set
of nucleotide prodrugs with varying substitution patterns. Extensive
formation of the triphosphate metabolite was observed in both rat
and human hepatocyte cultures. In addition, after oral dosing of several
phosphoramidate derivatives of compound <b>21</b> to rats, substantial
hepatic levels of the active triphosphate metabolite were found
Discovery and Early Development of TMC647055, a Non-Nucleoside Inhibitor of the Hepatitis C Virus NS5B Polymerase
Structure-based macrocyclization
of a 6-carboxylic acid indole
chemotype has yielded potent and selective finger-loop inhibitors
of the hepatitis C virus (HCV) NS5B polymerase. Lead optimization
in conjunction with in vivo evaluation in rats identified several
compounds showing (i) nanomolar potency in HCV replicon cells, (ii)
limited toxicity and off-target activities, and (iii) encouraging
preclinical pharmacokinetic profiles characterized by high liver distribution.
This effort culminated in the identification of TMC647055 (<b>10a</b>), a nonzwitterionic 17-membered-ring macrocycle characterized by
high affinity, long polymerase residence time, and broad genotypic
coverage. In vitro results of the combination of <b>10a</b> with
the HCV protease inhibitor TMC435 (simeprevir) supported an evaluation
of this combination in patients with regard to virus suppression and
resistance emergence. In a phase 1b trial with HCV genotype 1-infected
patients, <b>10a</b> was considered to be safe and well-tolerated
and demonstrated potent antiviral activity, which was further enhanced
in a combination study with TMC435