Cathepsin C (CTSC) inhibitor | BI-9740
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Highlights
BI-9740 is a very potent and highly selective inhibitor of the enzymatic activity of Cathepsin C. It blocks human CatC in vitro with an IC50 of 1.8 nM and shows > 1500x selectivity versus the related proteases Cathepsin B, F, H, K, L and S. BI-9740 displays no activity against 34 unrelated proteases from different classes up to a concentration of 10 µM.
BI-9740 fully inhibits the production of active neutrophil elastase in the human U937 cell line with an IC50 of 5.4 nM.
BI-9740 has very good in vitro and in vivo PK properties in several animal species (mouse, rat, mini pig). Treatment of mice with an oral formulation of BI-9740 for 11 consecutive days eliminates active neutrophil elastase in peripheral neutrophils with an ED50 of 0.05 mg/kg q.d. The levels of active Cathepsin G and Proteinase 3 are similarly reduced. More information about the compounds can be obtained via the “Contact us” formular (including slides of the oral presentation given by Marc Grundl at the ISyCatC II conference in Tour in 2019 - https://isycatc2019.sciencesconf.org).
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Target information
Cathepsin C (CatC) is a lysosomal cysteine protease. It is expressed at high levels in lung, kidney, and placenta and at moderate to low levels in many other organs. Among immune/inflammatory cells, the mRNA is expressed at high levels in polymorphonuclear leukocytes and alveolar macrophages and their precursor cells1.
In the bone marrow, CatC activates neutrophil serine proteases (NSPs) during myelopoiesis of neutrophils. Inhibition of CatC leads to a decrease in neutrophil elastase (NE), cathepsin G (CG), proteinase 3 (PR3) and NSP4 activities in circulating neutrophils. Inhibition of Cathepsin C can therefore be used to target pathophysiological processes triggered by enhanced or uncontrolled activity of these proteases2.
The active sites of CatC from human, rat, mouse, hamster and minipig are mostly conserved. Some non-conserved residues at the outer rim of the active site are not expected to largely influence inhibitor binding between species.
Figure 3: BI-9740, 3-D conformation
In vitro Activity
BI-9740 displays an IC50 = 1.8 nM in a biochemical humCatC assay and inhibits NE activity in U937 cell-lysate with an IC50 = 5.4 nM. BI-9740 possesses excellent selectivity toward CatK, CatS, CatL, CatB, CatH, CatF.
|
Probe name |
BI-9740 |
|
MW [Da] |
432 |
|
Human CatC + BSA (IC50) [nM]a |
1.8 |
|
NE activity in U937 cell-lysate (IC50) [nM] |
5.4 |
|
Mouse Cat C + BSA (IC50) [nM]a |
0.6 |
|
Rat Cat C + BSA (IC50) [nM]a |
2.6 |
|
Human CatK + BSA (IC50) [µM]a |
3.5 |
|
Human CatS + BSA (IC50) [µM]a |
32.6 |
|
Human CatL + BSA (IC50) [µM]a |
>30.0 |
|
Human CatH + BSA (IC50) [µM]a |
>100 |
|
Human CatB + BSA (IC50) [µM]a |
>100 |
|
Human CatF - BSA (IC50) [µM]a |
>100 |
a Assay conditions for CatC assay are available in the patent WO2014140075. For CatK, CatS, CatH, CatB and CatF the assay conditions are identical except for the enzyme nature, concentration, buffer and substrates. More detailed experimental conditions can always be obtained via the “Contact us” formular.
In vitro DMPK and CMC parameters
BI-9740 has high solubility at pH 2.2, 4.5 and 7. BI-9740 has very good in vitro PK properties in several animal species (mouse, rat, mini pig).
|
Probe name |
BI-9740 |
|
logP |
31 |
|
Solubility @ pH 6.8 [µg/ml] |
25 |
|
CACO permeability @pH7.4 [*10-6 cm/s] |
79 |
|
CACO efflux ratio |
1 |
|
MDCK permeability Pappa-b/b-a @ 1µM [10-6 cm/s] |
6.1 |
|
MDCK efflux ratio |
9.6 |
|
Microsomal stability (human/mouse/rat) [% QH] |
<23 | 39 | 80 |
|
Hepatocyte stability @ 5% plasma (human/mouse/rat) [% QH] |
<1 | 19 | 13 |
|
Plasma protein binding (human/mouse/rat) [%] |
98.5 | 97.7 | 99.9 |
|
hERG [inh. % @ 10 µM] |
39 |
|
CYP 3A4 (IC50) [µM] |
>50 |
|
CYP 2C8 (IC50) [µM] |
>50 |
|
CYP 2C9 (IC50) [µM] |
>50 |
|
CYP 2C19 (IC50) [µM] |
>50 |
|
CYP 2D6 (IC50) [µM] |
37 |
In vivo DMPK parameters
BI-9740 has in vivo PK properties in several animal species (mouse, rat, mini pig) allowing its testing in most of in vivo acute and chronic models.
|
BI-9740 |
MOUSE |
RAT |
MINI PIG |
|
Clearance [%QH]b |
5 |
0.6 |
4 |
|
Mean residence time after iv dose [h] |
2 |
5 |
3.7 |
|
tmax [h] |
0.3 (after oral dose 5 µmol/kg, natrosol) |
1.4 (after oral dose 5 µmol/kg, suspension) |
2.5 (after oral dose 10 µmol/kg, SUS/ADJ) |
|
Cmax [nM] |
655 |
5590 |
283 |
|
F [%] |
100 |
72 |
30 |
|
Vss [l/kg] |
0.54 |
0.12 |
0.38 |
b 0.43 [mg/kg]
In vivo pharmacology
A mouse model was used to demonstrate in vivo activity. In consideration of neutrophil homeostasis, animals were treated with BI-9740 once daily for 11 consecutive days. On day 12, animals were compound treated, followed by a LPS challenge by inhalation. Four hours later, bronchioalveolar lavage (BAL) was prepared and the activity of Neutrophile Elastase (NE) and of the related proteases Cathepsin G (CatG) and Proteinase 3 (PR3) in the lavage neutrophils was measured.
The production of active Neutrophil Elastase in peripheral neutrophils was completely attenuated by BI-9740 in a dose dependent manner with an ED50 of 0.05 mg/kg. The levels of active CatG and PR3 were similarly reduced.
|
ENZYME |
DOSE |
% REDUCTION VS LPS CONTROL |
|
NE |
0.5 mg/kg |
91 |
|
PR3 |
0.5 mg/kg |
97 |
|
CatG |
0.5 mg/kg |
100 |
Selectivity
BI-9740 shows a > 1000x selectivity versus the related proteases Cathepsin B, F, H, K, L and S and displays no activity against 34 unrelated proteases from different classes up to a concentration of 10 µM.
The testing of BI-9740 against 80 different receptors and transporters identified the following activities:
1) BI-9740 shows agonistic activity on the kappa opioid receptor (KOR) with an EC50 of 1.2 µM (protein-free assay).
2) BI-9740 shows inhibitory activity on the 5HT-transporter with an IC50 of 0.71 µM (protein-free assay).
|
BI-9740 |
SELECTIVITY DATA AVILABLE |
|
Cerep® |
Yes |
|
Panlabs® |
No |
|
Invitrogen® |
No |
|
DiscoverX® |
No |
|
Dundee |
No |
Co-crystal structure of the BI probe compound and the target protein
The Xray crystal structure of Cathepsin C in complex with BI-9740 is available via the “Contact us” form.
Figure 5: BI-9740, 3-D conformation co-crystalized in the CatC protein
reference molecules
Daniel Guay, Christian Beaulieu and David M. Percival Therapeutic Utility and Medicinal Chemistry of Cathepsin C Inhibitors Current Topics in Medicinal Chemistry 2010, 10, 2010, 708-716 DOI: 10.2174/156802610791113469, PubMed
Summary
BI-9740 is very potent, highly selective and orally bioavailable CatC inhibitor. BI-9740 shows no species selectivity and displays low nM IC50 in human, mouse and rat CatC assays. BI-9740 has high solubility at pH 2.2, 4.5 and 7. BI-9740 has very good in vitro and in vivo PK properties in several animal species (mouse, rat, mini pig).
Supplementary data
2 D structure formats available
Cathepsin C (CTSC) inhibitor | BI-9740.png
References
Human Dipeptidylpeptidase I Gene characterization, localization and expression
Narayanam V. Rao, Gopna V. Rao and John R. Hoidal
Journal of Biological Chemistry 1997, 272, 10260-10265.
Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases
Brice Korkmaz, Marshall S. Horwitz, Dieter E. Jenne and Francis Gauthier
Pharmcological Review 2010, 62, 726-759.
