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
T. A. Kelly et al.
J. Immunol. 1999;163:5173.
Second-Generation Lymphocyte Function Associated Antigen-1 Inhibitors: 1H-Imidazo[1,2-α]imidazol-2-one Derivatives
J.-P. Wu et al.
J. Med. Chem. 2004;47:5356.
The role of leukocyte function-associated antigen-1 in animal models of inflammation
R. J. Winquist et al.
Eur. J. Pharmacol. 2001;429:297.
An orally active, primate selective antagonist of LFA-1 inhibits delayed-type hypersensitivity in a humanized-mouse model
M. J. Panzerbeck et al.
Eur. J. Pharmacol. 2006;534:233.
Trans vivo Analysis of Human Delayed-Type Hypersensitivity Reactivity
L. Carrodeguas, C. G. Orosz, W. J. Waldmann, D. D. Sedmak, P. W. Adams, A. M. VanBuskirk
Human Immunology 1999;60:641-651.
Regiocontrolled synthesis of highly-functionalized fused imidazoles: a novel synthesis of second generation LFA-1 inhibitors
R. P. Frutos, M. Johnson
Tetrahedron Lett. 2003;44:6509.
Efficient Synthesis of a Small Molecule, Nonpeptide Inhibitor of LFA-1
X. Wang et al.
Org. Lett. 2010;12:4412.
Asymmetric Synthesis of LFA-1 Inhibitor BIRT2584 on Metric Ton Scale
X. Wang et al.
Org. Process Res. Dev. 2011;15:1185.
