B1 receptor antagonist
BI 113823
BI 113823 is a selective, potent Bradykinin 1 receptor antagonist1. It is highly soluble and presents a favorable PK profile, making it suitable for in vivo experiments. Its binding affinity for Bradykinin 2 receptor is from very weak to none, being selective versus a large panel of off-targets. The structurally similar BI-5832 can be used as a negative control.
More information
Bradykinin B1 Receptor (B1R) is a GPCR that has low expression in healthy tissues, however upon injury as well as in inflammatory conditions, higher expression is triggered. Particularly, chronic inflammation is linked with the protein expression. By binding to endogenous kinins, the signaling pathway activates phospholipase C that leads to increased intracellular calcium ion concentration leading to inflammatory responses.
Research has linked kinin B1 receptors to diverse pathological processes such as inflammation, platelet activation, smooth muscle contraction, increased vascular permeability, edema, pain, cytokine and chemokine release, cell proliferation, and tissue remodeling. The homolog, kinin B2 receptor, is expressed constitutively and play an important role in blood pressure regulation.
BI 113823 was seen to alleviate the pain-like behavior in preclinical settings. Dose dependent biological response was confirmed in rodent animal models.
Furthermore, BI 113823 shows efficacy in an experimental model of endotoxin-induced direct lung injury2 and was shown to reduce allergen-induced airway inflammation and mucus secretion in mice3.
Structure of the complex of the human Bradykinin-1 (B1) receptor (magenta) with [des-Arg10] -kallidin (white), the carboxy-terminal des-Arg metabolite of kallidin (PDB code 7EIB)4.
BI 113823 displays high affinity for the human B1 receptor determined by radioligand binding studies. Kallidin is displaced from human B1 with a Ki of 5.3 nM. Ki values of 13.3, 15.3 nM were measured for rat and rabbit, respectively. Thereby showing only little species differences – however no measurable affinity was observed for the pig B1R (Ki > 10 µM).
The compound does not exhibit any measurable binding for the human B2 receptor (Ki > 10 µM).
In addition, BI 113823 displays an IC50 value of 6.97 nM in a cellular assay. This is factor of 100 more potent than structurally similar negative control compound BI-5832. Finally, BI 113823 does not bind to B2 receptor.
| PROBE NAME / NEGATIVE CONTROL | BI 113823 | BI-5832 |
| MW [Da, free base]a | 524.7 | 520.7 |
| hB1R (Ki) [nM]b | 5.3 | 431.0 |
| hB2R (Ki) [nM]b | > 10,000 | n.a. |
| hB1R (IC50) [nM]c | 7.0 | 699.0 |
a For the salt form you will get, please refer to the label on the vial and for the molecular weight of the salt, please refer to the FAQs
b Membranes of CHO-K1 cells expressing human recombinant B1R. Non-specific binding is estimated in the presence of 10 µM Des-Arg9-(Leu8)-Bradykinin. Membranes are filtered and washed, the filters are then counted to determine [3H]Kallidin[des-Arg10, Leu9] specifically bound. Compounds are screened at 10 µM (Doods, H., Hauel, N., Arndt, K., Kramer, G., Ceci, A. Pain Prat 2012, 12 (Suppl. S1), 18).
c Measuring intracellular calcium in HEK-cells expressing human B1R, BI 113823 antagonizes the effects of the specific B1 agonist [Lys-des-Arg9]-Bradykinin (10 nM) in a concentration-dependent manner. No agonistic activity was observed with BI 113823, even at the highest concentration investigated (1 µM]).
Both the B1 receptor antagonist BI 113823 and the negative control BI-5832 are highly soluble compounds, metabolically stable and do not inhibit CYP proteins.
| PROBE NAME / NEGATIVE CONTROL | BI 113823 | BI-5832 |
| logD @ pH 11 | 2.5 | 3.22 |
| Solubility @ pH 6.8 [µg/mL] | >10,000.0 | 111 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 1.4 | < 1.7 |
| Caco-2 efflux ratio | 35.1 | n.a. |
| MDCK permeability PappAB @ 10µM [10-6 cm/s] | 6.3 | 0.6 |
| MDCK efflux ratio | 5.6 | 2 |
| Microsomal stability (human/rat/mouse) [% QH] | 42 / 44 / 39 | 53 / >88 / n.a. |
| Hepatocyte stability (human/rat/mouse) [% QH] | 38 / 51 / 42 | n.a. |
| Plasma Protein Binding (human) [%] | 92% | n.a. |
| hERG [inh. % @ 10 µM] | 6.9 | n.a. |
| CYP 3A4 (IC50) [µM] | > 50 | > 50 |
| CYP 2C8 (IC50) [µM] | > 50 | > 50 |
| CYP 2C9 (IC50) [µM] | > 50 | > 50 |
| CYP 2C19 (IC50) [µM] | > 50 | > 50 |
| CYP 2D6 (IC50) [µM] | > 50 | > 50 |
The pharmacokinetic profile of BI 113823 was obtained for rodent animals and is presented below.
| BI 113823 | MOUSEa | RATb |
| AUC0-inf [(nmol·h) / L] | 7240 | 2390 |
| tmax [h] | 0.25 | 0.5 |
| Cmax [nmol / L] | 3100 | 1230 |
| F [%] | 39.9 | 37.3 |
| Clearance [% QH] | 73c | 137c |
| Vss [L / kg] | 7.36c | 9.43c |
a Oral administration, 40 mg/kg, fed male
b Oral administration, 10 mg/kg, fasted male
c i.v. dose: 10 mg/kg
B1 receptor antagonist BI 113823 has been tested in different experimental conditions where signaling via B1 receptor is known to play a role. Results of experiments include:
- Reducing endotoxin-induced direct lung injury and sepsis-induced lung inflammatory response, as well as improved survival following severe polymicrobial sepsis2
- Reversing pre-existing severe experimental pulmonary hypertension in rat models5
- Preventing the increase of retinal vascular permeability in diabetic macular edema (DME) in rat models6
- Reducing systemic and tissue inflammatory responses, prevented hemodynamic derangement, attenuated multiorgan injury, and improved overall survival in rats7
- Reduction of mechanical hyperalgesia induced by complete Freund’s adjuvant mediated via antagonism of peripheral as well as spinal bradykinin B1 receptors8
- Reduction of postinfarction cardiac remodeling and heart failure9
- Improving post myocardial infarction cardiac function in rats10
BI-5832 is available as a negative control. The compound is structurally similar to BI 113823. The two compounds have comparable physicochemical and pharmacokinetic profile.
BI-5832, which serves as a negative control
BI 113823 was tested at the high concentration of 10µM on 69 targets in a selectivity panel and showed ≥1,000-fold selectivity for 67 targets (≤ 50% inhibition). In two assays (Sigma2/R, Sigma1/HU) the compound showed inhibition between 55 and 70%.
The negative control BI-5832 showed in 1 out of 44 targets inhibition with more than 50% @10 µM. It showed binding in Kappa-Opioid (KOP) assay with an inhibition of 58% @10 µM.
| SELECTIVITY DATA AVAILABLE | BI 113823 | BI-5832 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI113823_selectivityData.xlsx
BI-5832_selectivityData.xlsx
B1-Agonist [des-Arg10]-kallidin.
BI 113823 is a potent and selective Bradykinin 1 (B1) receptor antagonist. It shows an analgesic effect in chronic nociceptive pain conditions in preclinical animal models. The compound has shown very good solubility in aqueous media and an overall favorable pharmacokinetic profile. BI-5832 is available as a negative control.
When you plan a publication, please use the following acknowledgement:
BI-113823 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.