Danoprevir
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MedKoo CAT#: 315123

CAS#: 850876-88-9 (free base)

Description: Danoprevir, also known as ITMN-191 and RG-7227, is under development by InterMune Inc and Roche Holding AG, is a promising, potent NS3/4A protease inhibitor for the oral treatment of HCV infection. Preclinical data demonstrated that danoprevir binds with high affinity and dissociates slowly from the HCV NS3 protease, allowing high liver drug exposure with only modest plasma drug exposure. A phase Ib, 'IFN-free' clinical trial demonstrated that danoprevir, combined with the HCV polymerase inhibitor RG-7128 (Pharmasset Inc/Roche Holding AG), was effective in reducing HCV-RNA levels in a large proportion of treatment-naïve patients with HCV infection and in approximately half of previously non-responsive patients with HCV-1 infection, without resistance or safety concerns.


Chemical Structure

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Danoprevir
CAS# 850876-88-9 (free base)

Theoretical Analysis

MedKoo Cat#: 315123
Name: Danoprevir
CAS#: 850876-88-9 (free base)
Chemical Formula: C35H46FN5O9S
Exact Mass: 731.30003
Molecular Weight: 731.83
Elemental Analysis: C, 57.44; H, 6.34; F, 2.60; N, 9.57; O, 19.68; S, 4.38

Price and Availability

Size Price Availability Quantity
5.0mg USD 350.0 2 Weeks
10.0mg USD 550.0 2 Weeks
25.0mg USD 1250.0 2 Weeks
Bulk inquiry

Synonym: RG7227; RG 7227; RG-7227; ITMN191; ITMN-191; ITMN 191; RO5190591; RO-5190591; RO 5190591; Danoprevir;

IUPAC/Chemical Name: (2R,13aS,14aR,16aS,Z)-6-((tert-butoxycarbonyl)amino)-14a-((cyclopropylsulfonyl)carbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate

InChi Key: ZVTDLPBHTSMEJZ-QIFYYAQYSA-N

InChi Code: InChI=1S/C35H46FN5O9S/c1-34(2,3)50-32(45)37-27-13-8-6-4-5-7-11-22-17-35(22,31(44)39-51(47,48)24-14-15-24)38-29(42)28-16-23(19-41(28)30(27)43)49-33(46)40-18-21-10-9-12-26(36)25(21)20-40/h7,9-12,22-24,27-28H,4-6,8,13-20H2,1-3H3,(H,37,45)(H,38,42)(H,39,44)/b11-7-/t22-,23-,27?,28+,35-/m1/s1

SMILES Code: O=C(N1CC2=C(C(F)=CC=C2)C1)O[C@@H](C3)C[C@](C(N[C@@](C4)(C(NS(=O)(C5CC5)=O)=O)[C@]4([H])/C=C\CCCCCC6NC(OC(C)(C)C)=O)=O)([H])N3C6=O

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO.

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Product Data:

Biological target: Danoprevir (ITMN-191) is a NS3/4A protease inhibitor for hepatitis C virus (HCV) with an IC50 of 0.29 nM and is selective for NS3/4A over a panel of 53 proteases (IC50 higher than 10 μM).
In vitro activity: In peptide cleavage assays, ITMN-191 reduced genotype 1b NS3/4A (K2040) protease activity in a concentration-dependent fashion (Fig.2). In support of a slow/tight binding mechanism, suggested by Fig.2, NS3/4A activity was substantially lower in samples subjected to preincubation with 20 nM ITMN-191 than in samples with the same final enzyme and inhibitor concentrations that were not preincubated (Fig.3). Thus, ITMN-191 disassociated from genotype 1b NS3/4A with a half-life on the order of several hours, as evidenced by the persistence of inhibition over the same time scale. Dose-dependent reductions of a patient-derived HCV genotype 1b replicon harbored in hepatocyte-derived Huh7 cells were observed following 2-day incubation with ITMN-191 (Fig.4A). TMN-191 was a highly potent inhibitor of HCV replication in a cell-based system, as well as a highly potent inhibitor in biochemical assays. Treatment with 45 nM ITMN-191 (∼3 times its EC90) reduced HCV replicon RNA levels below the RT-PCR detection limit in a sustained fashion (Fig.4B) and completely cleared replicon RNA, as judged by the inability to select for replicon-containing cells in a 4-week follow-up period (Fig.4C). Reference: Antimicrob Agents Chemother. 2008 Dec; 52(12): 4432–4441. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592891/
In vivo activity: Doses of 30 mg/kg were administered to rats and monkeys via oral gavage, which corresponded to a human equivalent dose of 290 mg or 580 mg, respectively. Importantly, the concentrations of ITMN-191 observed in the livers of both species were significantly above the compound's EC50, although concentrations in rats were higher than in monkeys (Table 44 and Fig.6). In monkey liver tissue, the Cmax and C12 h were sufficient to reduce HCV replicon RNA by 3.1 log10 and 2.0 log10 units, respectively, and also resulted in HCV replicon clearance from cells in 14-day antiviral assays (Table4). While HCV is thought to replicate exclusively or nearly exclusively in the liver, significant reduction in HCV replicon RNA would also be supported by plasma concentrations (Table4). Thus, although the exposure of ITMN-191 in monkeys is lower than that observed in rats, concentrations achieved in the livers and plasma of both species would be predicted to significantly impair viral replication. These preclinical characteristics compare favorably to those of other inhibitors of NS3/4A in clinical development and therefore support the clinical investigation of ITMN-191 for the treatment of chronic hepatitis C. Reference: Antimicrob Agents Chemother. 2008 Dec; 52(12): 4432–4441. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2592891/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 90.0 122.98
Ethanol 80.0 109.32

Preparing Stock Solutions

The following data is based on the product molecular weight 731.83 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Seiwert SD, Andrews SW, Jiang Y, Serebryany V, Tan H, Kossen K, Rajagopalan PT, Misialek S, Stevens SK, Stoycheva A, Hong J, Lim SR, Qin X, Rieger R, Condroski KR, Zhang H, Do MG, Lemieux C, Hingorani GP, Hartley DP, Josey JA, Pan L, Beigelman L, Blatt LM. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother. 2008 Dec;52(12):4432-41. doi: 10.1128/AAC.00699-08. Epub 2008 Sep 29. PMID: 18824605; PMCID: PMC2592891.
In vitro protocol: 1. Seiwert SD, Andrews SW, Jiang Y, Serebryany V, Tan H, Kossen K, Rajagopalan PT, Misialek S, Stevens SK, Stoycheva A, Hong J, Lim SR, Qin X, Rieger R, Condroski KR, Zhang H, Do MG, Lemieux C, Hingorani GP, Hartley DP, Josey JA, Pan L, Beigelman L, Blatt LM. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother. 2008 Dec;52(12):4432-41. doi: 10.1128/AAC.00699-08. Epub 2008 Sep 29. PMID: 18824605; PMCID: PMC2592891.
In vivo protocol: 1. Seiwert SD, Andrews SW, Jiang Y, Serebryany V, Tan H, Kossen K, Rajagopalan PT, Misialek S, Stevens SK, Stoycheva A, Hong J, Lim SR, Qin X, Rieger R, Condroski KR, Zhang H, Do MG, Lemieux C, Hingorani GP, Hartley DP, Josey JA, Pan L, Beigelman L, Blatt LM. Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227). Antimicrob Agents Chemother. 2008 Dec;52(12):4432-41. doi: 10.1128/AAC.00699-08. Epub 2008 Sep 29. PMID: 18824605; PMCID: PMC2592891.

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1: Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S. Treatment of Chronic Hepatitis C Patients with the NS3/4A Protease Inhibitor Danoprevir (ITMN-191/RG7227) Leads to Robust Reductions in Viral RNA: A Phase 1b Multiple Ascending Dose Study. J Hepatol. 2010 Dec 8. [Epub ahead of print] PubMed PMID: 21145848.

2: Gane EJ, Roberts SK, Stedman CA, Angus PW, Ritchie B, Elston R, Ipe D, Morcos PN, Baher L, Najera I, Chu T, Lopatin U, Berrey MM, Bradford W, Laughlin M, Shulman NS, Smith PF. Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2010 Oct 30;376(9751):1467-75. Epub 2010 Oct 14. PubMed PMID: 20951424.

3: Thomas DL. Curing hepatitis C with pills: a step toward global control. Lancet. 2010 Oct 30;376(9751):1441-2. Epub 2010 Oct 14. PubMed PMID: 20951421.

4: Moucari R, Forestier N, Larrey D, Guyader D, Couzigou P, Benhamou Y, Voitot H, Vidaud M, Seiwert S, Bradford B, Zeuzem S, Marcellin P. Danoprevir, an HCV NS3/4A protease inhibitor, improves insulin sensitivity in patients with genotype 1 chronic hepatitis C. Gut. 2010 Dec;59(12):1694-8. Epub 2010 Sep 21. PubMed PMID: 20861007.

5: Deutsch M, Papatheodoridis GV. Danoprevir, a small-molecule NS3/4A protease inhibitor for the potential oral treatment of HCV infection. Curr Opin Investig Drugs. 2010 Aug;11(8):951-63. PubMed PMID: 20721837.