CETP inhibitor
BI-5756
BI-5756 is a highly potent and selective CETP inhibitor. It shows a robust elevation of HDL-C and reduction of LDL-C1. In contrast to anacetrapib, BI-5756 eliminates completely from fat tissues of hCETP transgenic mice 21 days after cessation of treatment. Additionally, BI-5756 shows no significant effects on aldosterone secretion from H295R cells1,2.
More information
Cholesteryl ester transfer protein (CETP) is a glycoprotein that is mainly secreted from the liver and circulates in plasma, mainly bound on HDP. It mediates the exchange of cholesteryl ester from HDL (high density lipoprotein) from apolipoprotein B (apoB) containing lipoproteins. This exchange results in increased LDL-C level in combination with decreased HDL-C levels3-5.
Given the recent evidence that the physiological role of HDL-C is more complex than previously thought6, there remains an interest to continue studying CETP inhibition.
X-ray structure of CETP with the inhibitor torcetrapib bound (PDB code 4EWS), indicating the binding location of CETP inhibitors in the lipid binding tunnel of CETP7.
BI-5756 inhibits the transfer of a fluorescence labelled lipid from donor vesicles to LDL with an IC50 of 145.5 nM. The negative control BI-9313 shows 19-fold less activity on the TransF Assay and 29-fold less activity on the TF_ROAR assay.
| Probe name / negative control | BI-5756 | BI-9313 |
| MW [Da]a | 475.5 | 475.5 |
| CETP TransF (IC50) [nM]b | 145.5 | 2794 |
| CETP-TF_ROAR (IC50) [nM] | 18 | 576 |
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
bFor assay conditions see Journal of Lipid Research, Volume 34, 1993; 1625-1634.
BI-5756 shows improved solubility and a reduction of logD. It also features moderate stability in human microsomes and hepatocytes.
| Probe name / negative control | BI-5756 | BI-9313 |
| logD @pH 11 | 5.9 | 6 |
| Solubility @ pH 6.8 [µg/mL] | 30 | < 1 |
| Caco-2 permeability AB @ pH 7.4 [*10-6 cm/s] | 68 | 41 |
| Caco-2 efflux ratio | 0.4 | 0.3 |
| Microsomal stability (human/mouse/rat) [% QH] | 24 / 51 / < 22 | < 23 / 39 / 55 |
| Hepatocyte stability (human/mouse/rat) [% QH] | 31 / 41 / 47 | n.a. |
| Plasma Protein Binding (human/mouse/rat) [%] | 99.5/ 99.7/ 99.1 | n.a. |
| hERG [IC50 (µM)] | 14.9 | n.a. |
| CYP 3A4 (IC50) [µM] | > 100 | > 50 |
| CYP 2C8 (IC50) [µM] | 15.1 | 13.1 |
| CYP 2C9 (IC50) [µM] | 16 | n.a. |
| CYP 2C19 (IC50) [µM] | 25.3 | > 50 |
| CYP 2D6 (IC50) [µM] | 18.2 | > 50 |
CETP is not expressed naturally in rodents. Based on its in vitro properties and its PK profile, BI-5756 was selected for in vivo evaluation. BI-5756 demonstrated dose-dependent CETP inhibition and HDL-cholesterol elevation in hCETP transgenic mice. BI-5756 shows a robust elevation of high-density lipoprotein-cholesterol (HDL-C) and reduction of low-density lipoprotein-cholesterol (LDL-C) in hCETP/hApoB-100 mice1. In contrast to the CETP inhibitor anacetrapib, BI-5756 eliminated completely from tissues of hCETP transgenic mice 21 days after cessation of treatment for 5 days at a fully efficacious dose. Unlike the CETP inhibitor torcetrapib, BI-5756 showed no significant effects on aldosterone secretion from the H295R human adrenal carcinoma cell line up to 10 μM.
Target Exposure of anacetrapib and BI-5756 in different tissues of male hCETP transgenic mice. Measure at day 3 and day 21 after cessation of oral treatment for 5 days (either 10mg/kg of anacetrapib or 3mg /kg of BI-5756).
| Probe name / negative control | BI-5756 |
| Clearance [mL/(min*kg)] (mouse)a | 16.0 |
| Mean residence time after i.v. dose [h] (mouse) | 6.1 |
| tmax [h]b (mouse / rat) | 0.9 / 2 |
| Cmax [nM]b (mouse / rat) | 387.8 / 345 |
| F [%] (mouse) | 46 |
| Vss [L/kg] (mouse) | 5.9 |
a i.v. dose: 0.5 mg/kg
b p.o. dose: 3 mg/kg
BI-9313 is the enantiomer of the BI-5756 and is offered as a negative control with low binding affinity to the CETP inhibitor.
BI-9313 serves as a negative control.
Selectivity is not considered to be crucial. Nonetheless, BI-5756 was tested on 104 targets in a selectivity panel and showed ≥1,000-fold selectivity for 93 targets (≤ 50% inhibition @ 10 µM). In 11 assays, the compound showed inhibition ≥ 51. It showed, for example, activity on Cannabinoid receptor CB1 (0.93 µM) and CB2 (0.66 µM).
The negative control BI-9313 showed in 4 out of 44 targets inhibition with more than 50% @ 10 µM (e.g. PDE4D2 and CB1).
| SELECTIVITY DATA AVAILABLE | BI-5756 | BI-9313 |
|---|---|---|
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | No | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-5756_selectivityData.xlsx
BI-9313_selectivityData.xlsx
anacetrapib
BI-5756 is a potent, polar cholesteryl ester transfer protein (CETP) inhibitor. It has a reduced lipophilicity and improved solubility compared to other CETP inhibitors, with a fast elimination from fat tissues of hCETP transgenic mice1. It also shows a robust elevation of HDL-C and reduction of low-density lipoprotein-cholesterol in physiological models, with good DMPK properties. Its enantiomer BI-9313 is available as a negative control.
Potent Cholesteryl Ester Transfer Protein Inhibitors of Reduced Lipophilicity: 1,1′-Spiro-Substituted Hexahydrofuroquinoline Derivatives.
Trieselmann T., Wagner H., Fuchs K., Hamprecht D., Berta D., Cremonesi P., Streicher R., Luippold G., Volz A., Markert M., Nar H.
J. Med. Chem. 2014, 57, 8766–8776.
Evaluation of Lipids, Drug Concentration, and Safety Parameters Following Cessation of Treatment With the Cholesteryl Ester Transfer Protein Inhibitor Anacetrapib in Patients With or at High Risk for Coronary Heart Diseas
Gotto A. M., Cannon C. P., Li X. S., Vaidya S., Kher U., Brinton E. A., Davidson M., Moon J. E., Shah S., Dansky H. M., Mitchel Y., Barter P.
Am. J. Cardiol. 2014, 113, 76–83.
When you plan a publication, please use the following acknowledgement:
BI-5756 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://www.opnme.com.