LTB4 receptor antagonist
BIIL 315
BIIL 315 is a highly potent and selective LTB4 receptor antagonist. This compound binds with high affinity to the LTB4 receptor (Ki = 1.9 nM) and shows good metabolic stability in vitro. It is an excellent tool to study LTB4 signaling in vitro1. The prodrug BIIL 284, which is also available on opnMe.com, should be used for in vivo studies.
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The LTB4 receptor is a G-protein coupled receptor (GPCR) with high affinity specifically to Leukotriene B4 (LTB4), which is a dihydroxy fatty acid formed from arachidonic acid by the 5-lipoxygenase pathway2. LTB4 is one of the most powerful mediators involved in inflammatory processes. Binding of LTB4 to the receptor particularly activates neutrophilic leukocytes and triggers chemotaxis, degranulation and oxidative burst. In particular, neutrophilic leukocytes are readily attracted and activated by LTB4, producing an accumulation of neutrophils and also macrophages, T lymphocytes and eosinophils at the site of inflammation. Thus, LTB4 has been suggested to be an important participant in the pathophysiology of inflammatory processes of many human diseases with unmet medical need. The inhibition of LTB4 has caused a reduction of inflammatory processes in various diseases models in vivo1,2.
A crystal structure of the LTB4 receptor was published in 2018 by Hori et al.3.
Crystal structure of LTB4 receptor with BIIL 2603
Due to its prodrug character, BIIL 284 displays negligible affinity to the LTB4 receptor (Ki = 230 nM). BIIL 315 (Ki = 1.9 nM), which is formed from BIIL 284, however, binds with high affinity to the LTB4 receptor. BIIL 315 potently inhibits LTB4-induced intracellular Ca2+ release in human neutrophils (IC50 value of 0.75 nM) as measured with Fura-21. In the presence of 0.1% BSA, the inhibitory potency was reduced by 6-fold due to protein binding. Additionally, BIIL 315 (IC50 = 0.65 nM) potently inhibits LTB4-induced chemotaxis of human polymorphonuclear leukocytes (PMNLs)1. LTB4 receptor kinetic analysis of BIIL 315 revealed slow off-dissociation. The Ki value calculated from the kinetic is 4 pM for BIIL 315 on human neutrophil granulocyte membranes. Consequently, BIIL 315 is the dominating LTB4 antagonist in vivo and a highly potent in vitro tool4. The negative control BIIS 035 did not display any binding affinity and can be used for in vitro experiments.
| Probe name | BIIL 284 | BIIL 315 | BIIS 035 |
| MW [Da]a | 538.6 | 642.7 | 610.7 |
| LTB4 receptor binding (Ki) [nM]b | 230 | 1.9 | >1000 |
| Inhibition of LTB4-induced Ca2+ (IC50) [nM]b | --- | 0.75 | --- |
| Inhibition of LTB4-induced chemotaxis in human PMNLs (IC50) [nM]b | --- | 0.65 | --- |
aFor the salt form you will get, please refer to the label on the vial andn for the molecular weight of the salt, please refer to the FAQs
bAssay conditions are described in reference 1;
BIIL 315 displays good metabolic stability in vitro. However, it should not be used in vivo. Please use BIIL 284 for in vivo studies, which is also available on opnMe.
| Probe name | BIIL 315 | BIIS 035 |
| LogD @ pH2 / pH 7.4 / pH11 | 2.14 / n.a. / 2.16 | 4.2 / >6 |
| Solubility @ pH 7 [µg/mL] | <1.0 | <1.0 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | <0.01 | <0.1 |
| Microsomal stability (human/mouse/rat) [% QH] | n.a. / <23 / <22 | 61 / n.a. / 61 |
| Plasma Protein Binding (hum/mouse/rat) [% QH] | 99.7 / 99.9 / 99.8 | n.a. |
in vivo studies revealed BIIL 315 as the dominating active metabolite in rats after p.o. administration of BIIL 284. For in vivo studies please use the in vivo prodrug BIIL 284, which is also available on opnMe.
| BIIL315 | RAT |
| Clearance [mL/min/kg]a | 8.3 |
| Mean residence time after i.v. dose [h] | 0.31 |
| tmax [h]b | 2.0 |
| Cmax [nM] | 4800 |
| F [%] | 7.5 |
| Vss [L/kg] | 0.15 |
| AUC0-∞ [ng*h/ml] | 13000 |
| t½ | 3.1 |
ai.v. dose: 0.92 mg/kg
bp.o. dose: 70 mg/kg as a solution in Labrasol
The efficacy of BIIL 315 has been demonstrated in various in vivo LTB4 models by p.o. administration of the in vivo prodrug BIIL 284. These models comprised
- Inhibition of LTB4-induced mouse ear inflammation (ED50 = 0.0082 mg/kg p.o.)
- Inhibition of LTB4-induced transdermal chemotaxis in guinea pigs (ED50 = 0.028 mg/kg p.o.)
For more details, please see reference 11.
In addition, BIIL 284 and its metabolite BIIL 315 have been investigated in disease models for asthma, rheumatoid arthritis and skin inflammation. The compound demonstrated significant efficacy in a collagen induced arthritis mouse model and reduced the antigen-induced eosinophilic bronchial influx in guinea pigs (asthma model). In the skin inflammation model a psoriasis like dermatitis LTB4-induced skin effects can be antagonized with BIIL 284. Furthermore, BIIL 284 and its metabolite BIIL 315 counteracts with arachidonic acid induced skin inflammation in mice, however dermatitis is not blocked completely4.
BIIS 035 displays no affinity to the LTB4 receptor and therefore can be used as negative control for in vitro experiments.
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BIIL 315 is a selective LTB4 antagonist with no relevant off-target effects in the Eurofins Safety Panel 44™.
| SELECTIVITY DATA AVAILABLE | BIIL 315 | BIIS 035 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BIIL-315_selectivityData_0.xlsx
BIIS035_selectivityData.xlsx
A crystal structure of leukotriene B4 receptor in complex with BIIL 260 was published by Hori et al. (PDB code: 5X33)3.
BIIL 315 was identified as the major component in plasma after p.o. administration and appears to be the dominating LTB4 antagonist of BIIL 284 in vivo. The major site of metabolism seems to be localized primarily in the gut wall. Thereby, ubiquitous esterases will convert BIIL 284 to BIIL 260, which will be further glucuronidated by UDP-glucuronyl-tranferases. Consequently, p.o. administration of BIIL 284 will lead to BIIL 315 by fast metabolism. Intravenous administration of BIIL 284 and BIIL 260 will lead only to minor formation of the more potent BIIL 315 metabolite. Furthermore, BIIL 284 displays very low solubility causing crystallization of the compound in plasma. Combining these two aspects, BIIL 284 should only be used as in vivo tool using p.o. administration4.
BIIL 315 is a highly potent LTB4 receptor antagonist (Ki = 1.9 nM)1. It is the active metabolite of the in vivo tool compound BIIL 284 and is the ideal tool to study LTB4 antagonism in vitro. Additionally, BIIS 035 is available as negative control for in vitro experiments.
In vitro and in vivo pharmacological characterization of BIIL 284, a novel and potent leukotriene B(4) receptor antagonist
Birke FW., Meade CJ., Anderskewitz R., Speck GA., Jennewein HM.
J Pharmacol Exp Ther. 2001, 297(1), 458-66.
IND 58361 SN 000 OA V01
Leukotriene B4 receptor antagonist LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells.
Tong WG., Ding XZ., Hennig R., Witt RC., Standop J., Pour PM., Adrian TE.
Clin Cancer Res. 2002, 8(10), 3232-42.
Inhibition of leukotriene B4-induced CD11B/CD18 (Mac-1) expression by BIIL 284, a new long acting LTB4 receptor antagonist, in patients with rheumatoid arthritis.
Alten R., Gromnica-Ihle E., Pohl C., Emmerich J., Steffgen J., Roscher R., Sigmund R., Schmolke B., Steinmann G.
Ann Rheum Dis. 2004, 63(2), 170-6.
When you plan a publication, please use the following acknowledgement:
BIIL 315 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.