Hepatitis C virus (HCV) NS3 protease inhibitor | BI-1230
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Highlights
BI-1230 binds to the active site of NS3 that is located in the shallow and broad protein-protein interaction surface of the protease and the helicase domain of the enzyme. It is a single digit nanomolar inhibitor of protease activity and of viral replication that was shown to be highly selective against other serine/cysteine proteases. Pharmacokinetic evaluation shows good half-life and bioavailability, making BI-1230 a valuable in vitro and in vivo tool compound.
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Target 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-1230 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 infection.4
In vitro Activity
|
Probe name / Negative control |
BI-1230 |
BI-1675 |
|
MW [Da] |
817 |
669 |
|
IC50 [nM]a |
6.7 |
4870 |
|
EC50 [nM], replicon assay, genotype 1ab |
4.6 |
n.d. |
|
EC50 [nM], replicon assay, genotype 1bb |
<1.8 |
n.d. |
a Enzymatic assay, NS3-NS4A heterodimer, fluorogenic substrate, 60 min incubation
b Cell-based HCVPV RNA replication Luciferase reporter assay, genotype background 1a and 1b, Huh7 cells, 72 h incubation
In vitro DMPK parameters
|
Probe name |
BI-1230 |
|
Solubility @ pH 7 [µg/ml] |
20 |
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
8.7 |
|
CACO efflux ratio |
0.3 |
|
Microsomal stability [% QH] |
<24 |
|
Plasma protein binding human [%] |
99.9 |
In vivo DMPK parameters
In vivo DMPK parameters of BI-1230 in rat, dog, and cynomolgus monkeya
|
Route |
BI-1230 |
rat |
dog |
monkey |
|
i.v. |
CL [ml/min/kg] |
15 |
1.9 |
1.2 |
|
Mean residence time after iv dose [h] |
2.3 |
3.4 |
6.6 |
|
|
Vss [l/kg] |
2.05 |
0.39 |
0.49 |
|
|
p.o. |
t1/2 [h] |
2.1 |
5.1 |
8.9 |
|
tmax [h] |
1.8 |
1.7 |
4.0 |
|
|
Cmax [nM] |
405 |
7370 |
3930 |
|
|
AUC0-inf [nM*h] |
2550 |
49700 |
38330 |
|
|
F [%] |
42 |
92 |
45 |
a Dose = i.v., 2 mg/kg; p.o., 5 mg/kg
Negative control
BI-1675 can be used as inactive in vitro control compound.
BI-1675, negative control
Selectivity
BI-1230 is highly selective against other serine/cysteine proteases.
Data from selectivity assay panels currently not available.
Co-crystal structure of the BI probe compound and the target protein
An X-ray structure of BI-1230 in complex with NS3 is not available. However, the structure with the highly related BI 201335 was solved.
X-ray structure of HCV NS3 protease with BI 201335, a close analog of BI-1230 (PDB code: 3p8n)
reference molecules
For a recent review of HCV NS3 protease inhibitors see reference 5.
Summary
BI-1230 is a single digit nanomolar inhibitor of HCV NS3 protease activity and of viral replication. BI-1230 was shown to be highly selective against other serine/cysteine proteases and to be suitable for in vivo studies.
Supplementary data
References
Macrocyclic Inhibitors of the NS3 Protease as Potential Therapeutic Agents of Hepatitis C Virus Infection
Tsantrizos Y. S., Bolger G., Bonneau P., Cameron D. R., Goudreau N., Kukolj G., LaPlante S. R., Llinàs-Brunet M., Nar H., Lamarre D.
Angw. Chem. Int. Ed. 2003, 42, 1355-1360.
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.
WO 2005/028501A1, US 8552205
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.
Hepatitis C virus NS3/4a protease inhibitors
McCauley A. J., Rudd T. M.
Curr. Opin. Pharmacol. 2016, 30, 84-92.
