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ITMN-191

Cat. No. M1844

ITMN-191 Structure

Synonym: Danoprevir, RG7227

Size Price Availability Quantity
2mg USD 95 In stock
5mg USD 150 In stock
10mg USD 240 In stock
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Quality Control
  • Current batch:
  • Purity >99%
  • COA
  • MSDS
Biological Activity

ITMN-191 (Danoprevir, RG7227) is a potent and orally active inhibitor of hepatitis C virus (HCV) NS3/4A serine protease with an IC50 of 1.6 nM. ITMN-191 is shown to be a potent inhibitor of NS3 with a two-step binding mechanism. Progress curves are consistent with the formation of an initial collision complex (EI) that isomerizes to a highly stable complex (EI*) from which ITMN-191 dissociates very slowly. From progress curve analysis, the rate constant for dissociation of ITMN-191 from the EI* complex is 3.8 x 10(-5) s(-1) with a calculated complex half-life of approximately 5 h and a true biochemical potency (K(i)*) of approximately 62 pM. Abrogation of the tight binding and slow dissociative properties of ITMN-191 is observed with proteases that carry the R155K or D168A substitution, each of which is likely in compound resistant mutants. Slow dissociation is not observed with closely related macrocyclic inhibitors of NS3, suggesting that members of this class may display distinct binding kinetics.

Protocol
Cell Experiment
Cell lines Huh7 cells
Preparation method The viability of Huh7 cells, human cardiac myocytes, and human cardiac fibroblasts was assessed following 72 h of exposure to ITMN-191 using a CellTiter-Glo Luminescent Cell Viability kit (Promega, Madison, WI). For these cell types, viability in the presence of ITMN-191 was fitted to a four-parameter logistic function to obtain a 50% cytotoxic concentration (CC50). Additionally, the CC50s were determined for six primary normal human cell types in stationary and proliferating (dividing) phases by Lonza, Inc. (Walkersville, MD). The cell types included normal human hepatocytes, microvascular endothelial cells, human skeletal muscle myoblasts, human articular chondrocytes, human lung fibroblasts, and renal proximal tubule epithelial cells. For the proliferating phase, ITMN-191 was added when cells reached 50% confluence. For the stationary phase, ITMN-191 was added 1 day after cells reached 100% confluence. Cell viability was quantified following 72 h of exposure to ITMN-191 using a ViaLight Plus kit on a microplate reader. CC50s were determined as described above.
Concentrations 5 pM ~100 nM
Incubation time 72 h
Animal Experiment
Animal models Sprague-Dawley rats and Cynomolgus monkeys
Formulation water
Dosages 30-mg/kg
Administration oral gavage
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 731.83
Formula C35H46FN5O9S
CAS Number 850876-88-9
Purity >99%
Solubility DMSO ≥100 mg/mL
Ethanol ≥100 mg/mL
Storage at -20°C
References

Characterization of HCV quasispecies dynamics upon short term dual-therapy with the HCV NS5B nucleoside polymerase inhibitor mericitabine and the NS3/4 protease inhibitor danoprevir.
Le Pogam et al. Antimicrob Agents Chemother. 2012 Aug 6. PMID: 22869576.

Understanding the drug resistance mechanism of hepatitis C virus NS3/4A to ITMN-191 due to R155K, A156V, D168A/E mutations: A computational study.
Pan et al. Biochim Biophys Acta. 2012 Oct;1820(10):1526-34. PMID: 22698669.

Impact of low-dose ritonavir on danoprevir pharmacokinetics: results of computer-based simulations and a clinical drug-drug interaction study.
Reddy et al. Clin Pharmacokinet. 2012 Jul 1;51(7):457-65. PMID: 22624502.

Sustained virological response after 14-day treatment with danoprevir and 48-week treatment with pegylated interferon-α2a (40 KD) plus ribavirin.
Larrey et al. Antivir Ther. 2012;17(5):927-32. PMID: 22611092.

Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227).
Seiwert SD, et al. Antimicrob Agents Chemother. 2008 Dec;52(12):4432-41. PMID: 18824605.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: ITMN-191, Danoprevir, RG7227 supplier, Proteasome, inhibitors

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