LFA-1 antagonist | BI-1950
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Highlights
BI-1950 potently inhibits the binding of LFA-1 to ICAM-1 (intercellular adhesion molecule 1) with a KD value of 9 nM and the production of IL-2 in human PBMC and whole blood with an IC50 value of 3 nM and 120 nM, respectively. BI-1950 shows >1000 fold selectivity against the most closely related b2-integrin Mac-1 and b1-integrin function and has an attractive DMPK profile, making it a excellent molecule for testing pharmacological hypotheses in vitro and in vivo.
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Target information
The integrin LFA-1 (lymphocyte function-associated antigen-1) is a receptor present on lymphocytes that plays, together with its major ligand ICAM-1 (intercellular adhesion molecule 1), an important role in immune cell function.1,3,4
X-Ray structure of LFA-1 with an analogue of BI-1950 (solved at Boehringer Ingelheim)
In vitro Activity
BI-1950 potently inhibits the binding of LFA-1 to ICAM-1 with a KD value of 9 nM.
|
Probe name / Negative control |
BI-1950 |
BI-9446 |
|
Molecular weight [Da] |
646.5 |
602.5 |
|
Inhibition of LFA-1 binding to ICAM-1 KD [nM]a |
9 |
>1000 |
|
Inhibition of SEB-induced production of IL-2 in human PBMC IC50 [nM]b |
3 |
>1000 |
|
Inhibition of SEB-induced production of IL-2 in human whole blood IC50 [nM]b |
120 |
n.d. |
a Binding assay
b SEB: staphylococcal enterotoxin B
In vitro DMPK parameters
|
Probe name / Negative control |
BI-1950 |
BI-9446 |
|
Solubility @ pH 6.8 [µg/ml] |
0.9 µg/mL |
0.1 µg/mL |
|
CACO permeability @ pH 7.4 [*10-6 cm/s] |
13 |
n.d. |
|
CACO efflux ratio |
2 |
n.d. |
|
Stability in liver microsomes (human / mouse / rat) [% QH] |
13 / 12 / 6 |
n.d. |
|
Stability in human hepatocytes [% QH] |
6 |
n.d. |
|
Plasma protein binding (human / mouse / dog) |
99.6 / 99.7 / 99.9 |
n.d. |
In vivo DMPK parameters
|
BI-1950 |
Mouse |
Rat |
|
CL (IV) [% QH] |
8 |
11 |
|
Vss [L/kg] |
3.3 |
2.7 |
|
MRT [h] |
7.2 |
6.5 |
|
F [%] |
154 |
21 |
In vivo pharmacology
BI-1950 shows an attractive DMPK profile and was tested in a proof-of-concept model in vivo. As BI-1950 demonstrates greater than 250-fold selectivity for human over mouse LFA-1 as assessed in paired assays that measure the inhibition of IL-2 production in SEB-stimulated human PBMC and mouse splenocytes (SEB: staphylococcal enterotoxin B), a trans vivo model for delayed type hypersensitivity (DTH) in SCID mice was used.5 After injection of human PBMCs into the footpad of SCID mice and stimulation with a specific antigen (tetanus toxoid, TT), the DTH response is quantified by measuring the footpad swelling. BI-1950 inhibited swelling in a dose dependent manner and showed full efficacy at a dose of 3 mg/kg PO.
Negative control
BI-9446, negative control of BI-1950
The close analog BI-9446 can be used as negative control for in vitro studies with much weaker affinity to LFA-1 (> 1µM).
Selectivity
In an external selectivity screen at Eurfins (Panlabs®) BI-1950 hit 4/47 targets >50 % Inhibition @ 10 µM. See supplementary information for details.
Selectivity data available
| Molecule name |
BI-1950 |
|
Cerep® |
No |
|
Eurofins-Panlabs® |
Yes |
|
Invitrogen® |
No |
|
DiscoverX® |
No |
|
Dundee |
No |
Co-crystal structure of the BI probe compound and the target protein
No Xray structure is available for BI-1950 but for the structurally related compound ( 17d in J. Med. Chem. 2004;47:5356).2
Summary
BI-1950 potently inhibits the binding of LFA-1 to ICAM-1 with a KD value of 9 nM and the production of IL-2 in human PBMC and whole blood with an IC50 value of 3 nM and 120 nM, respectively.
Supplementary data
2 D structure formats available
LFA-1 (lymphocyte function-associated antigen-1) antagonist | BI-1950.png
LFA-1 (lymphocyte function-associated antigen-1) antagonist | BI-1950.smiles
LFA-1 (lymphocyte function-associated antigen-1) antagonist | BI-1950.sdf
Negative control | BI-9446.png
References
Cutting Edge: A Small Molecule Antagonist of LFA-1-Mediated Cell Adhesion
Kelly T. A., Jeanfavre D. D., McNeil D. W., Woska J. R. Jr, Reilly P. L., Mainolfi E. A., Kishimoto K. M., Nabozny G. H., Zinter R., Bormann B. J., Rothlein R.
J. Immunol. 1999, 163, 5173.
Second-Generation Lymphocyte Function Associated Antigen-1 Inhibitors: 1H-Imidazo[1,2-α]imidazol-2-one Derivatives
Wu J. P., Emeigh J., Gao D. A., Goldberg D. R., Kuzmich D., Miao C., Potocki I., Qian K. C., Sorcek R. J., Jeanfavre D. D., Kishimoto K., Mainolfi E. A., Nabozny G. Jr., Peng C., Reilly P., Rothlein R., Sellati R. H., Woska J. R. Jr., Chen S., Gunn J. A., O'Brien D., Norris S. H., Kelly T. A.
J. Med. Chem. 2004, 47, 5356.
The role of leukocyte function-associated antigen-1 in animal models of inflammation
Winquist R. J., Desai S., Fogal S., Haynes N. A., Nabozny G. H., Reilly P. L., Souza D., Panzenbeck M.
Eur. J. Pharmacol. 2001, 429, 297-302
An orally active, primate selective antagonist of LFA-1 inhibits delayed-type hypersensitivity in a humanized-mouse model
Panzenbeck M. J., Jeanfavre D. D., Kelly T. A., Lemieux R., Nabozny G., Reilly P. L., Desai S.
Eur. J. Pharmacol. 2006, 534, 233.
Trans vivo Analysis of Human Delayed-Type Hypersensitivity Reactivity
Carrodeguas L., Orosz C. G., Waldmann W. J., Sedmak D. D., Adams P. W., VanBuskirk A. M.
Human Immunology 1999, 60, 641-651.
Regiocontrolled synthesis of highly-functionalized fused imidazoles: a novel synthesis of second generation LFA-1 inhibitors
Frutos R. R, Johnson M.
Tetrahedron Lett. 2003, 44, 6509.
Efficient Synthesis of a Small Molecule, Nonpeptide Inhibitor of LFA-1
Wang X. J., Xu Y., Zhang L., Krishnamurthy D., Wirth T., Nicola T., Senanayake C. H.
Org. Lett. 2010, 12, 4412.
Asymmetric Synthesis of LFA-1 Inhibitor BIRT2584 on Metric Ton Scale
Wang X. J.,Frutos R. P., Zhang L., Sun X., Xu Y., Wirth T., Nicola T., Nummy L. J., Krishnamurthy D., Busacca C. A., Yee N., Senanayake C. H.
Org. Process Res. Dev. 2011, 15, 1185.
Papers with our molecules. Published by you.
List of externally generated publications upon the public release of our molecules via opnMe.com. In case you think your paper is missing, please contact us.
Impedance-based analysis of Natural Killer cell stimulation
Fasbender F., Watzl C.
Scientific Reportsvolume 8, Article number: 4938 (2018)
