Hepatitis C virus (HCV) NS3 protease inhibitor | BI-1230

Target protein: 
HCV NS3
Probe Name: 
BI-1230
MOLECULAR WEIGHT [DA]: 
817.0
In stock: 
857

Chemical structure

2D Structure of BI-1230

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.

X-ray structure of HCV NS3 protease with BI 201335, a close analog of BI-1230 (PDB code: 3p8n)

X-ray structure of HCV NS3 protease with BI 201335, a close analog of BI-1230 (PDB code: 3p8n)

3D structure of BI-1230

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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

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
669.0

BI-1675 can be used as inactive in vitro control compound.

BI-1675, negative control

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

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

  1. Macrocyclic Inhibitors of the NS3 Protease as Potential Therapeutic Agents of Hepatitis C Virus Infection

    Youla S. Tsantrizos, Gordon Bolger, Pierre Bonneau, Dale R. Cameron, Nathalie Goudreau, George Kukolj, Steven R. LaPlante, Montse Llinàs-Brunet, Herbert Nar, Daniel Lamarre

    Angw. Chem. Int. Ed. 2003;42:1355-1360.

  2. A Highly Convergent and Efficient Synthesis of a Macrocyclic Hepatitis C Virus Protease Inhibitor BI 201302

    Xudong Wei, Chutian Shu, Nizar Haddad, Xingzhong Zeng, Nitinchandra D. Patel, Zhulin Tan, Jianxiu Liu, Heewon Lee, Sherry Shen, Scot Campbell, Richard J. Varsolona, Carl A. Busacca, Azad Hossain, Nathan K. Yee, and Chris H. Senanayake

    Org. Lett. 2013;15:1016-1019.

  3. WO 2005/028501A1, US 8552205

  4. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

    Daniel Lamarre, Paul C. Anderson, Murray Bailey, Pierre Beaulieu, Gordon Bolger, Pierre Bonneau, Michael Bös, Dale R. Cameron, Mireille Cartier, Michael G. Cordingley, Anne-Marie Faucher, Nathalie Goudreau, Stephen H. Kawai, George Kukolj, Lisette Lagacé, Steven R. LaPlante, Hans Narjes, Marc-André Poupart, Jean Rancourt, Roel E. Sentjens, Roger St George, Bruno Simoneau, Gerhard Steinmann, Diane Thibeault, Youla S. Tsantrizos, Steven M. Weldon, Chan-Loi Yong, Montse Llinàs-Brunet

    Nature 2003;426:186-189.

  5. Hepatitis C virus NS3/4a protease inhibitors

    J. A. McCauley, T. M. Rudd

    Curr. Opin. Pharmacol. 2016;30:84-92.