LFA-1 antagonist | BI-1950

Target protein: 
LFA-1
Probe Name: 
BI-1950
MOLECULAR WEIGHT [DA]: 
646.5
In stock: 
538

Chemical structure

2D Structure of BI-1950

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.

3D structure of BI-1950

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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)

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

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
602.5

BI-9446, negative control of BI-1950

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

Download selectivity data: 

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

References

  1. Cutting Edge: A Small Molecule Antagonist of LFA-1-Mediated Cell Adhesion

    T. A. Kelly et al.

    J. Immunol. 1999;163:5173.

  2. 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.

  3. The role of leukocyte function-associated antigen-1 in animal models of inflammation

    R. J. Winquist et al.

    Eur. J. Pharmacol. 2001;429:297.

  4. 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.

  5. 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.

  6. 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.

  7. Efficient Synthesis of a Small Molecule, Nonpeptide Inhibitor of LFA-1

    X. Wang et al.

    Org. Lett. 2010;12:4412.

  8. Asymmetric Synthesis of LFA-1 Inhibitor BIRT2584 on Metric Ton Scale

    X. Wang et al.

    Org. Process Res. Dev. 2011;15:1185.