Danoprevir

Medication

None

Legal statusLegal status

Investigational

Identifiers

IUPAC name

(2R,6S,12Z,13aS,14aR,16aS)-6-[(tert-Butoxycarbonyl)amino]-14a-[N-(cyclopropanesulfonyl)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-fluoro-1,3-dihydro-2H-isoindole-2-carboxylate

CAS Number

850876-88-9

PubChem CID

56841889

ChemSpider

9460579

UNII

911Z9PCQ5F

KEGG

D09884

ChEMBL

ChEMBL2311191

NIAID ChemDB

488730

PDB ligand

TSV (PDBe, RCSB PDB)

Chemical and physical dataFormulaC₃₅H₄₆FN₅O₉SMolar mass731.84 g·mol⁻¹3D model (JSmol)

SMILES

CC(C)(C)OC(=O)N[C@@H]1CCCCC\C=C/[C@@H]2C[C@]2(NC(=O)[C@@H]3C[C@H](CN3C1=O)OC(=O)N4Cc5cccc(F)c5C4)C(=O)NS(=O)(=O)C6CC6

InChI

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
Key:ZVTDLPBHTSMEJZ-UPZRXNBOSA-N

Danoprevir (INN)^[1] is an orally available^[2] 15-membered macrocyclic peptidomimetic inhibitor of NS3/4A HCV protease.^[3] It contains acylsulfonamide, fluoroisoindole and tert-butyl carbamate moieties. Danoprevir is a clinical candidate based on its favorable potency profile against multiple HCV genotypes 1–6 and key mutants (GT1b, IC₅₀ = 0.2–0.4 nM; replicon GT1b, EC₅₀ = 1.6 nM).^[4] Danoprevir has been evaluated in an open-label, single arm clinical trial in combination with ritonavir for treating COVID-19^[5] and favourably compared to lopinavir/ritonavir in a second trial.^[6]

History

Danaoprevir was initially developed by Array BioPharma then licensed to Roche for further development and commercialization. In 2013, Danoprevir was licensed to Ascletis by Roche for development and production in China under the tradename Ganovo.^[7]^[8]

References

^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 64" (PDF). World Health Organization. p. 265. Retrieved 25 February 2017.
^ Deutsch M, Papatheodoridis GV (August 2010). "Danoprevir, a small-molecule NS3/4A protease inhibitor for the potential oral treatment of HCV infection". Current Opinion in Investigational Drugs. 11 (8): 951–63. PMID 20721837.
^ Jiang Y, Andrews SW, Condroski KR, Buckman B, Serebryany V, Wenglowsky S, et al. (March 2014). "Discovery of danoprevir (ITMN-191/R7227), a highly selective and potent inhibitor of hepatitis C virus (HCV) NS3/4A protease". Journal of Medicinal Chemistry. 57 (5): 1753–69. doi:10.1021/jm400164c. PMID 23672640.
^ Levin J, ed. (2015). "7.4.1 Danoprevir (ITMN-191)". Macrocycles in Drug Discovery. The Royal Society of Chemistry. doi:10.1039/9781782623113. ISBN 978-1-84973-701-2.
^ Chen H, Zhang Z, Wang L, Huang Z, Gong F, Li X; et al. (2020). "First clinical study using HCV protease inhibitor danoprevir to treat COVID-19 patients". Medicine (Baltimore). 99 (48): e23357. doi:10.1097/MD.0000000000023357. PMC 7710192. PMID 33235105.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Zhang Z, Wang S, Tu X, Peng X, Huang Y, Wang L; et al. (2020). "A comparative study on the time to achieve negative nucleic acid testing and hospital stays between danoprevir and lopinavir/ritonavir in the treatment of patients with COVID-19". J Med Virol. 92 (11): 2631–2636. doi:10.1002/jmv.26141. PMC 7300667. PMID 32501538.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^ Ng E (17 July 2018). "Singapore sovereign wealth fund GIC to invest US$75 million in Chinese drug maker Ascletis' Hong Kong IPO". South China Morning Post. Retrieved 10 Aug 2018.
^ Speights K (21 February 2017). "How High Can Array BioPharma Inc. Stock Go?". The Motley Fool. Retrieved 13 August 2018.

Seiwert SD, Andrews SW, Jiang Y, Serebryany V, Tan H, Kossen K, et al. (December 2008). "Preclinical characteristics of the hepatitis C virus NS3/4A protease inhibitor ITMN-191 (R7227)". Antimicrobial Agents and Chemotherapy. 52 (12): 4432–41. doi:10.1128/AAC.00699-08. PMC 2592891. PMID 18824605.

RNA virus antivirals (primarily J05, also S01AD and D06BB)

Hepatitis C

NS3/4A protease inhibitors (–previr)	Asunaprevir Boceprevir^‡ Ciluprevir^§ Danoprevir^† Faldaprevir^‡ Glecaprevir Grazoprevir Narlaprevir Paritaprevir Simeprevir Sovaprevir^† Telaprevir^‡ Vaniprevir Vedroprevir^§ Voxilaprevir
NS5A inhibitors (–asvir)	Coblopasvir Daclatasvir^# Elbasvir Ledipasvir Odalasvir^† Ombitasvir Pibrentasvir Ravidasvir^† Ruzasvir^† Samatasvir^† Velpatasvir
NS5B RNA polymerase inhibitors (–buvir)	Beclabuvir^† Bemnifosbuvir^† Dasabuvir^# Deleobuvir^§ Filibuvir^§ GS-6620^§ IDX-184^§ Setrobuvir^§ Sofosbuvir^# Tegobuvir^§ TMC-647055^§ Radalbuvir^† Uprifosbuvir^†
Combination drugs	Elbasvir/grazoprevir Glecaprevir/pibrentasvir Ledipasvir/sofosbuvir^# Ombitasvir/paritaprevir/ritonavir^# Sofosbuvir/daclatasvir Sofosbuvir/velpatasvir^# Sofosbuvir/velpatasvir/voxilaprevir

Hepatitis D

Bulevirtide

Picornavirus

viral entry: Pleconaril^†

Anti-influenza agents

neuraminidase inhibitors/release phase (Oseltamivir^#
Zanamivir
Peramivir, Laninamivir^†)

Multiple/general

Interferon	Interferon alfa 2b Peginterferon alfa-2a^# Peginterferon alfa-2b^#
3CL protease inhibitors (–trelvir)	Ensitrelvir^† Lufotrelvir Nirmatrelvir^† (+ritonavir)^† Rupintrivir Simnotrelvir (+ritonavir^†)
RNA pol inhibitors	CMX521^§ Deuremidevir^† Favipiravir Galidesivir^† GS-441524^§ Remdesivir MK-608^§ Mericitabine^† Molnupiravir NITD008^§ Ribavirin^# Taribavirin^† Triazavirin Valopicitabine^†
Multiple/Unknown/Other	EICAR^§ Merimepodib^§ Moroxydine Presatovir^†