Chymase inhibitor | BI-1942
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Highlights
BI-1942 is a highly potent inhibitor of human chymase (IC50 = 0.4 nM) that can be used to test biological hypotheses involving this target in vitro. With BI-1829 we also offer a structurally close analog that is more than 1000 fold less active (IC50 = 850 nM) and can thus be used as negative control for in vitro studies.
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Target information
Chymase plays an important and diverse role in the homeostasis for a number of cardiovascular processes and has been linked to heart failure. Chymase is a chymotrypsin-like serine protease that is stored in a latent form in the secretory granules of mast cells. Upon stimulation, it is released in its active form into the local tissue, contributing to the activation of TGF-ß, matrix metalloproteases and cytokines. Cardiac chymase has been shown to be involved in the formation of angiotensin II and to play an important role in activating TGF-ß1 and IL-1ß, generating endothelin, altering apolipoprotein metabolism and degrading the extracellular matrix.
Chymase in complex with a close analog of BI-1942 (Boehringer Ingelheim internal structure).
In vitro Activity
| Probe name / Negative control | BI-1942 | BI-1829 |
| MW [Da] | 434.5 | 419.5 |
| Inhibition of human chymase IC50 [nM]* | 0.4 | 850 |
a for detailed assay conditions see reference 1
In vitro DMPK and CMC parameters
|
Probe name / Negative control |
BI-1942 |
BI-1829 |
|
Solubility @ pH 7.4 [µg/ml] |
> 93 |
n.d. |
|
Solubility @ pH 4.5 [µg/ml] |
50 |
n.d. |
|
Microsomal stability (human/mouse/rat) [% QH] |
< 30 |
n.d. |
|
Plasma protein binding (human) [%] |
97.3 |
n.d. |
Negative control
Structurally related BI-1829 shows much weaker inhibition of human Chymase (IC50 = 850 nM) and therefore is a suitable negative control for in vitro experiments.
BI-1829 which serves as a negative control
Selectivity
BI-1942 is more than 100-fold selective against cathepsin G (IC50 = 110 nM)*.
Selectivity data from external assay panels is not available
*For detailed assay conditions please refer to Reference 1.
Co-crystal structure of the BI probe compound and the target protein
Co-crystal structure of the Boehringer Ingelheim probe compound and the target protein.
No X-ray co-crystal structure with BI-1942 is available. For a structurally related compound an X-ray structure was solved at Boehringer Ingelheim (see Figure 3).
reference molecules
For reference molecules see Reference 4.
Summary
Chymase plays an important and diverse role in the homeostasis for a number of cardiovascular processes and has been linked to heart failure. BI-1942 is a potent inhibitor of human chymase with an IC50 value of 0.4 nM and >100 fold selectivity against Cathepsin G and is thus a suitable tool for testing biological hypotheses involving human Chymase in vitro.
Supplementary data
References
Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategy
Taylor S. J., Padyana A. K., Abeywardane A., Liang S., Hao M.-H., De Lombaert S., Proudfoot J, Farmer 3rd B. S., Li X., Collins B., Martin L., Albaugh D. R., Hill-Drzewi M., Pullen S. S.,Takahashi H.
J. Med. Chem. 2013, 56, 4465.
Benzimidazolone as potent chymase inhibitor; Modulation of reactive metabolite formation in the hydrophobic (P1) region
Loa H. Y., Nemotoa P. A., Kima J. M., Haoa M.-H., Qiana K. C., Farrowa N. A., Albaughd D. R., Fowlerb D. M., Schneidermanb R. D., Augustc E. M., Martinc L., Hill-Drzewic M., Pullen S. S., Takahashia H., De Lombaerta S.
Bioorg. Med. Chem. Lett. 2011, 21, 4533.
Chymase Inhibition and Cardiovascular Protection
Tojo H., Urata H.
Cardiovasc Drugs Ther, 2013, 27, 139.
Chymase inhibitors
Yahiro E., Miura S., Imaizumi S., Uehara Y., Saku K.
Chymase inhibitors Curr. Pharm. Des. 2013, 19, 3065.
