HCV protease inhibitor
BI-1388
BI-1388 is a highly selective inhibitor of HCV NS3 protease. It binds to the active site of NS3 and inhibits protease activity and viral replication with nanomolar to picomolar potency across various HCV genotypes and resistant mutants D168V and R155K. BI-1388 demonstrated high selectivity against other serine/cysteine proteases and it is characterized by exceptional liver partitioning.
More information
HCV NS3 protease is a 180-amino acid chymotrypsin-like serine protease. Its function is the auto-proteolytic cleavage of HCV viral polyprotein (~3000 aa) into individual, non-structural (NS) proteins with various functions. Thus it is an essential component of HCV replication and infectivity. The NS3 protein contains two functional domains: a serine protease- and a helicase domain. The active site of NS3 is located in the shallow and wide protein-protein interaction surface of these domains. BI-1388 and other known NS3 inhibitors cover significant parts of this interaction surface in addition to the active site. Boehringer Ingelheim was the first company to establish proof-of-concept in humans for an HCV NS3 protease inhibitor as a treatment of HCV infection4.
BI-1388 bound to the active site of NS3 (PDB code: 4i31)3
| Probe name | BI-1388 |
| MW [Da]a | 820.0 |
| IC50 [nM]b, WT enzyme, genotype 1a | 0.48 |
| IC50 [nM]b, WT enzyme, genotype 1b | 1.1 |
| IC50 [nM]a, WT enzyme, genotype 2a | 0.14 |
| IC50 [nM]b, WT enzyme, genotype 3a | 12 |
| IC50 [nM]b, WT enzyme, genotype 4a | 0.23 |
| IC50 [nM]b, WT enzyme, genotype 5a | 0.24 |
| IC50 [nM]b, WT enzyme, genotype 6a | 0.16 |
| IC50 [nM]b, R155K, genotype 1a | 4.7 |
| IC50 [nM]b, D168V, genotype 1a | 58 |
| IC50 [nM]b, A156T, genotype 1b | 2.7 |
| IC50 [nM]b, D156V, genotype 1b | 4.3 |
| IC50 [nM]b, D168A, genotype 1b | 16 |
| IC50 [nM]b, D168V, genotype 1b | 15 |
| EC50 [nM], WT, replicon assay, genotype 1ac | 0.11 |
| EC50 [nM], R155K, replicon assay, genotype 1ac | 1.0 |
| EC50 [nM], WT, replicon assay, genotype 1bc | 0.11 |
| EC50 [nM], D168V, replicon assay, genotype 1bc | 0.14 |
aFor 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
bEnzymatic assay, see ref. 3 for assay details
cCell-based HCV RNA replication Luciferase reporter assay, see ref. 3 for assay details
| Probe name | BI-1388 |
| LogD @ pH 11 | 2.3 |
| Solubility @ pH 7 [µg/ml] | 3.4 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 10 |
| Caco-2 efflux ratio | 1.2 |
| Hepatocyte stability (human) [%QH] | 20 |
| Plasma Protein Binding (human,mouse) [% QH] | 99.8 / 99.8 |
| CYP 1A2 (IC50) [µM] | >30 |
| CYP 2C9 (IC50) [µM] | 6.4 |
| CYP 2C19 (IC50) [µM] | >30 |
| CYP 2D6 (IC50) [µM] | >30 |
Pharmacokinetic profile of BI-1388 in rat.
| Route | BI-1388 | Rat |
| i.v.a | Clearance [mL/min/kg] | 19 |
| t1/2 (h) | 2.6 | |
| Vss [L/kg]b | 0.97 | |
| F(%) | 14 | |
| p.o.b | Cmax(µM) | 1.3 |
| AUC0-inf[nM*h) | 1.4 |
ai.v. dose: 3.3 mg/kg (70% PEG-400 and 30% water)
bp.o. dose: 4.1 mg/kg (1% MP, 0.3% Tween-80, and Methocel 0.5%)
| SELECTIVITY DATA AVILABLE | BI-1388 |
SafetyScreen44™ with kind support of  | Yes |
| Invitrogen® | No |
| DiscoverX® | No |
| Dundee | No |
Download selectivity data:
BI-1388_selectivityData.xlsx
An X-ray structure of BI-1388 in complex with NS3 is available (PDB code: 4i31, 4i32, 4i33 – complexes with WT and resistant mutants D168V and R155K)
For a recent review of HCV NS3 protease inhibitors see reference 6.
BI-1388 is a highly selective inhibitor of NS3 protease with nanomolar potency across various Hepatitis C Virus (HCV) genotypes and against resistant mutants D168V and R155K.
A Highly Convergent and Efficient Synthesis of a Macrocyclic Hepatitis C Virus Protease Inhibitor BI 201302
Wei X., Shu C., Haddad N., Zeng X., Patel N. D., Tan Z., Liu J., Lee H., Shen S., Campbell S., Varsolona R. J., Busacca C. A., Hossain A., Yee N. K., Senanayake C. H.
Org. Lett. 2013, 15, 1016-1019.
An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus
Lamarre D., Anderson P. C., Bailey M., Beaulieu P., Bolger G., Bonneau P., Bös M., Cameron D. R., Cartier M., Cordingley M. G., Faucher A. M., Goudreau N., Kawai S. H., Kukolj G., Lagacé L., LaPlante S. R., Narjes H., Poupart M. A., Rancourt J., Sentjens R. E., St George R., Simoneau B., Steinmann G., Thibeault D., Tsantrizos Y. S., Weldon S. M., Yong C. L., Llinàs-Brunet M.
Nature 2003, 426, 186-189.
Discovery of Hepatitis C Virus NS3-4A Protease Inhibitors with Improved Barrier to Resistance and Favorable Liver Distribution
Moreau B., O’Meara J. A., Bordeleau J., Garneau M., Godbout C., Gorys V., Leblanc M., Villemure E., White P. W., Llinàs-Brunet M.
J. Med. Chem. 2014, 57, 1770-1776.
When you plan a publication, please use the following acknowledgement:
BI-1388 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.