HCV NS5B polymerase inhibitor
BI 207127
BI 207127 also known as Deleobuvir is a highly potent and specific inhibitor of GT-1 HCV NS5B polymerase. It inhibits the enzymatic function of NS5B by binding to pocket 1 of its thumb domain and, in turn, inhibits viral replication of HCV. With its good ADME-PK profile, this compound is suitable for both in vitro and in vivo experiments. BI-207127 has been successfully tested in clinical trials, where it showed good tolerability and high antiviral potency against HCV infection.
More information
HCV NS5B is an RNA-dependent RNA polymerase that is essential for the replication of the genome of the hepatitis c virus. BI 207127 inhibits the polymerase activity by binding to pocket 1 of the thumb domain of NS5B - the exact molecular mechanism of this allosteric inhibition is unknown.
It shows weak or no inhibition in specificity assays that include poliovirus RdRp, mammalian DdRp II, and DNA polymerase α, β, and γ. Moreover, the interferon-free combination of our NS3 protease inhibitor faldaprevir with BI 207127 and ribavirin has demonstrated high efficacy and good tolerability in GT1b treatment-naive patients in phase II clinical trials. However, efficacy against GT1a has proven suboptimal in more recent trials, leading to the discontinuation of the development of BI 207127 as an anti-HCV drug.
Hepatitis C virus polymerase in complex with an inhibitor bound to thumb-domain pocket 1 (PDB code: 4gmc)
BI 207127 is a highly potent and specific inhibitor of genotype(GT)-1 HCV polymerase activity (IC50 = 50 nM) and with antiviral activity (EC50 values of 11 and 23 nM in cell-based replicon GT1b and GT1a assays, respectively).
in vitro activity table
| PROBE NAME / NEGATIVE CONTROL | BI 207127 | BI-7656 |
| MW [Da, free base]a | 653.6 | 487.6 |
| IC50 [nM]b | 19 | >5000 |
| EC50 [nM], replicon assay, genotype 1ac | 23 | n.d. |
| EC50 [nM], replicon assay, genotype 1bc | 11 | n.d. |
a For the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
b Enzymatic assay, HCV NS5B polymerase D21, SPA measuring 3H-UTP incorporation
c Cell-based replicon assay using RT-PCR for RNA quantification, genotype background 1a and 1b, Huh7 cells, 72 h incubation
BI 207127 is a permeable but poorly soluble tool compound with moderate microsomal stability. Efforts to improve the solubility led to the discovery of BI-7656, the negative control.
| PROBE NAME / NEGATIVE CONTROL | BI 207127 | BI-7656 |
| logP/logD @ pH | 1.9 | 0.8 |
| Solubility @ pH 7 [µg/mL] | 11 | n. a. |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 15 | n. a. |
| Caco-2 efflux ratio | 0.5 | n. a. |
| Hepatocyte clearance t1/2 (human) [min] | 256 | n. a. |
| Plasma Protein Binding human [%] | 99.6 | n. a. |
Summary of pharmacokinetic parameters for Deleobuvir in plasmaa
| BI 207127 | RAT |
| Clearance [mL/min/kg]a | 1.2 |
| t½ [h]b | 4.4 |
| tmax [h] | 3.5 |
| Cmax [nM] | 18000 |
| AUC0–inf [nMh] | 60000 |
| F [%]] | 31 |
ai.v. dose: 0.5 mg/kg
bp.o. dose: 1 mg/kg
Two major metabolites of deleobuvir were identified in plasma: an acyl glucuronide and an alkene reduction metabolite formed in the gastrointestinal (GI) tract by gut bacteria (CD 6168), representing 20% and 15% of the total drug-related material, respectively. For additional details please see Chen et al 6.
BI-7656
| SELECTIVITY DATA AVILABLE | BI 207127 | BI-7656 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI%20207127_selectivityData.xlsx
BI-7656_selectivityData.xlsx
While the X-ray structure of NS5B in complex with BI 207127 was not solved, structures with other pocket 1-binding allosteric inhibitors are available (example: 4gmc.pdb; see section “Target Information”). A model of the NS5B:BI 207127 complex was built based on such structures (see reference 4 for details).
BI 207127 (Deleobuvir) was an investigational drug against HCV infection, successfully tested in clinical trials, with good tolerability.
HCVerso: An Open-Label, Phase IIb Study of Faldaprevir and Deleobuvir with Ribavirin in Hepatitis C Virus Genotype-1b-Infected Patients with Cirrhosis and Moderate Hepatic Impairment
Sarrazin C., Manns M., Calleja J. L., Garcia-Samaniego J., Forns X., Kaste R., Bai X., Wu J., Stern J. O.
PLoS One 2016, v11, e0168544.
Faldaprevir, deleobuvir and ribavirin in IL28B non-CC patients with HCV genotype-1a infection included in the SOUND-C3 phase 2b study
Zeuzem S., Mantry P., Soriano V., Buynak R. J., Dufour J. F., Pockros P. J., Wright D., Angus P., Buti M., Stern J. O., Kadus W., Vinisko R., Böcher W., Mensa F. J.
Eur J Gastroenterol Hepatol. 2016, 28, 923-926.
Antiviral Effect, Safety, and Pharmacokinetics of Five-Day Oral Administration of Deleobuvir (BI 207127), an Investigational Hepatitis C Virus RNA Polymerase Inhibitor, in Patients with Chronic Hepatitis C
Larrey D., Lohse A. W., Trepo C., Bronowicki J. P., Arastéh K., Bourlière M., Calleja J. L., Stern J. O., Nehmiz G., Abdallah N., Berger K. L., Marquis M., Steffgen J., Kukolj G., BI 207127 Study Group.
Antimicrob. Agents Chemother. 2013, 57, 4727-4735.
Conformation-based restrictions and scaffold replacement in the design of hepatitis C virus polymerase inhibitors: discovery of deleobuvir (BI 207127)
LaPlante S. R., Bös M., Brochu C., Chabot C., Coulombe R., Gillard J. R., Jakalian A., Poirier M., Rancourt J., Stammers T., Thavonekham B., Beaulieu P. L., Kukolj G., Tsantrizos Y. S.
J. Med. Chem. 2014, 57, 1845-1854.
The liver partition coefficient corrected inhibitory quotient and the pharmacokinetic-pharmacodynamic relationship of directly acting anti-hepatitis C virus agents in humans
Duan J., Bolger G., Garneau M., Amad M., Batonga J., Montpetit H., Otis F., Jutras M., Lapeyre N., Rhéaume M., Kukolj G., White P. W., Bethell R. C.,Cordingley M. G.
Antimicrob. Agents Chemother. 2012, 56, 5381−5386.
Viral Polymerase Inhibitors
Tsantrizos Y., Chabot C., Beaulieu P., Brochu, C. Poirier M., Stammers T., Bounkham T., Rancourt J.
WO2005080388 A1, 2005.
Mass Balance, Metabolite Profile, and In Vitro-In Vivo Comparison of Clearance Pathways of Deleobuvir, a Hepatitis C Virus Polymerase Inhibitor
Chen L. Z., Sabo J. P., Philip E., Rowland L., Mao Y., Latli B., Ramsden D., Mandarino D. A., Sane R. S.
Antimicrob. Agents Chemother. 2015, 59, 25-37.
When you plan a publication, please use the following acknowledgement:
BI 207127 (Deleobuvir) was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.