Autotaxin (ATX) inhibitor | BI-2545
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Highlights
BI-2545 inhibits human ATX with an 50 of 2.2 nM. In human whole blood BI-2545 inhibits Autotaxin with an 50 of 29 nM and in rat whole blood with an 50 of 96 nM.6 In vivo BI-2545 demonstrated after a single oral dose to rats at 10 mg/kg a LPA reduction of up to 90%. We also offer BI-3017 as inactive control.
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Target information
Autotaxin (ATX) is a secreted phosphodiesterase that hydrolyzes the abundant phospholipid lysophosphatidylcholine (LPC) to produce lysophosphatidic acid (LPA). Recent studies suggest that the ATX-LPA axis is highly implicated in a number of pathophysiological diseases including inflammation, cancer and idiopathic pulmonary fibrosis.
BI-2545 bound to ATX (X-ray structure solved at Boehringer Ingelheim)
In vitro Activity
In vitro activity table
|
Probe name / Negative control |
BI-2545 |
BI-3017 |
|
MW [Da] |
527.4 |
407.4 |
|
hATX LPA 50 [nM] |
2.2 |
8900 |
|
rat whole blood 50 [nM] |
96 |
n.d. |
|
human whole blood (50) [nM] |
29 |
n.d. |
In vitro DMPK parameters
In vitro DMPK parameters table
|
Probe name |
BI-2545 |
|
Solubility @ pH 6.8 [µg/ml] |
<1 |
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
9.32 |
|
CACO efflux ratio |
1.41 |
|
Human hepatocyte clearance [% QH] |
22 |
|
Plasma protein binding human [%] |
n.d. |
In vivo DMPK parameters
In vivo DMPK parameters table
|
Probe name |
BI-2545 |
|
Rat PK (i.v.): |
|
|
CL [mL/(min*kg)] |
7 |
|
CL [% QH)] |
10 |
|
MRT [h] |
2.1 |
|
Vss [L/kg] |
0.9 |
|
Rat PK (p.o.): |
|
|
Cmax [nM] |
92 |
|
tmax [h] |
1.7 |
|
MRT [h] |
4.5 |
|
F [%] |
30 |
Negative control
Chemical structure of the negative control BI-3017
Selectivity
Selectivity data available
|
Probe name |
BI-2545 |
|
Cerep® |
Yes |
|
Eurofins-Panlabs® |
No |
|
Invitrogen® |
No |
|
DiscoverX® |
No |
|
Dundee |
No |
Co-crystal structure of the BI probe compound and the target protein
The X-ray co-crystal structure of ATX with BI-2545 will be published (paper submitted).
reference molecules
See reference 1
Summary
BI-2545 inhibits human ATX with an 50 of 2.2 nM. In human whole blood BI-2545 inhibits Autotaxin with an 50 of 29 nM and in rat whole blood with an 50 of 96 nM.
Supplementary data
References
Discovery, Structure-Activity Relationship, and Binding Mode of an Imidazo[1,2-a]pyridine Series of Autotaxin Inhibitors
Joncour A., Desroy N., Housseman C., Bock X., Bienvenu N., Cherel L., Labeguere V., Peixoto C., Annoot D., Lepissier L., Heiermann J., Hengeveld W. J., Pilzak G., Monjardet A., Wakselman E., Roncoroni V., Le Tallec S., Galien R., David C., Vandervoort N., Christophe T., Conrath K., Jans M., Wohlkonig A., Soror S., Steyaert J., Touitou R., Fleury D., Vercheval L., Mollat P., Triballeau N., van der Aar E., Brys R., Heckmann B.
J. Med. Chem. 2017, 60, 6480-6515.
Development of Autotaxin Inhibitors: An Overview of the Patent and Primary Literature
Castagna D., Budd D. C., Macdonald S. J., Jamieson C., Watson A. J.
J. Med. Chem. 2016, 59, 5604-5621.
Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions
Benesch M. G. K., Ko Y. M., McMullen T. P. W., Brindley D. N.
FEBS Letters, 2014, 588, 2712-2727.
Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design
Jones S. B., Pfeifer L. A., Bleisch T. J., Beauchamp T. J., Durbin J. D., Klimkowski V. J., Hughes N. E., Rito C. J., Dao Y., Gruber J. M., Bui H., Chambers M. G., Chandrasekhar S., Lin C., McCann D. J., Mudra D. R., Oskins J. L., Swearingen C. A., Thirunavukkarasu K., Norman B. H.
ACS Med. Chem. Lett. 2016, 7, 857-861.
Autotaxin: structure-function and signalling
Perrakis A., Moolenaar W. H.
J. Lipid Res. 2014, 55, 1010-1018.
Discovery of BI-2545: A Novel Autotaxin Inhibitor That Significantly Reduces LPA Levels in Vivo ACS
Kuttruff C. A., Ferrara M., Bretschneider T., Hoerer S., Handschuh S., Nosse B., Romig H., Nicklin P., Roth G. J.
Med. Chem. Lett. 2017, 8, 1252-1257
