FLAP antagonist | BI 665915
Highlights
BI-665915 is a selective and highly potent 5‑Lipoxygenase Activating Protein (FLAP) antagonist (IC50 = 1.7 nM). A favorable cross-species drug metabolism and attractive DMPK profile, with low i.v. plasma clearance and good oral bioavailability, make it an excellent tool for studying the LT pathway both in vitro and in vivo. BI-665915 has been shown to potently inhibit LTB4 production in mouse and human whole blood.
Background information
Target Information
5‑Lipoxygenase Activating Protein (FLAP) is an important protein in the Leukotriene (LT) pathway which acts as a partner of 5-lipoxygenase (5-LO) in the metabolism of arachidonic acid.3
Human FLAP in complex with leukotriene synthesis inhibitors (PDB code: 2q7r)
Leukotriene (LT) Pathway1
The membrane-attached 5-lipoxygenase activating protein (FLAP) binds to arachidonic acid (AA) and selectively transfers AA to 5-lipoxygenase (5-LO), which oxidizes AA to 5-hydroperoxyeicosatetraenoic acid (5-HpETE) followed by a dehydration to LTA4.1,3
Leukotrienes (LTs) are a family of eicosanoid proinflammatory mediators that are biosynthesized from arachidonic acid (AA) via oxidative metabolism.3
The leukotriene pathway constitutes a series of events underlying the inflammatory components of several diseases such as asthma, allergy, and atherosclerosis.3,5,6
More information about the target can be found in the following J. Med. Chem. publication1 by Hidenori Takahashi et al. and references cited therein.
In vitro activity
BI 665915 shows a high potency (IC50 = 1.7 nM in the FLAP binding assay).
In vitro activity table
| Probe name / negative control | BI 665915 | BI-0153 |
| MW [Da] | 459 | 430 |
| FLAP binding (IC50) [nM]a | 1.7 | 670 |
| FLAP Functional inhibition in human whole blood (IC50) [nM]b | 45 | >5000 |
| FLAP Functional inhibition in mouse whole blood (IC50) [nM]c | 4800 | n.d. |
a Binding assay; geometric mean values (n ≥ 3), each determined from duplicate 10-point concentration−response curves;
b Human whole blood assays; geometric mean values (n ≥ 3), each determined from duplicate 10-point concentration−response curves;
c Mouse whole blood assays performed using the same protocol as that for the hWB assay; geometric mean values (n ≥ 3), each determined from duplicate 8-point concentration−response curves
In vitro DMPK and CMC parameters
In vitro DMPK parameters table
| Probe name / negative control | BI 665915 | BI-0153a |
| Solubility @ pH 6.8 [µg/ml] | 48 | >43 |
| CACO permeability @ pH 7.4 [*10-6 cm/s] | 34 | n.d. |
| CACO efflux ratio | 1.9 | n.d. |
| Human hepatocyte clearance [% QH] | 41 | n.d. |
| Plasma protein binding human [% QH] | 95.3 | n.d. |
a Please refer to the section negative control
In vivo DMPK parameters
BI 665915 was evaluated in rats, dogs, and cynomolgus monkeys (see table). The compound showed low i.v. plasma clearance over the three species and a good bioavailability of 45 to 63%.
In mice high exposures were observed at a dose of 100 mg/kg (AUC0-inf = 436,000 nM*h).
In vivo DMPK parameters of BI 665915 in the rat, dog, and cynomolgus monkeya
| BI 665915 | rat | dog | monkey |
| CL [% QH]b,c | 7.0 | 2.8 | 3.6 |
| Mean residence time after i.v. dose (l/kg)b | 3.1 | 23 | 4.8 |
| F [%]b | 63 | 58 | 45 |
| Vss [l/kg]b | 0.9 | 1.2 | 0.5 |
a Dose = i.v., 1 mg/kg; dosing vehicle, 70% PEG; p.o., 10 mg/kg; dosing suspension vehicle, 0.5% methyl cellulose/0.015% Tween; all DMPK parameters were determined after 11-time point blood sampling (0, 5, 15, 30 min, 1, 2, 4, 6, 8, 12, and 24h) per i.v. or p.o. dose.
b Mean values (n = 3).
c Value represents the percentage of hepatic blood flow.
In vivo pharmacology
BI 665915 shows an attractive DMPK profile and therefore was tested in a mouse ex vivo model of mechanism engagement. Blood samples were stimulated with calcimycin, and the levels of LTB4 were measured. BI 665915 demonstrated dose-dependent LTB4 production inhibition in mouse whole blood, 2 h after a single oral dose.1
Negative control
Negative control
The closely related analogue BI-0153 can be used as an in vitro negative control
Selectivity
Extensive external screens covering 751 targets did not give strong hits (see supplementary data section)
Invitrogen® panel: 546 kinases < 30% inhibition @ 3µM
Eurofins Safety Panel 44™ External screen covering 68 targets @ 10 µM
Eurofins Safety Panel 44™ External screen covering 137 targets @ 20 µM
| SELECTIVITY DATA AVILABLE | BI 665915 | BI-0153 |
SafetyScreen44™ with kind support of  | Yes | Yes |
| Invitrogen® | Yes | No |
| DiscoverX® | No | No |
| Dundee | No | No |
Download selectivity data:
BI-665915_selectivityData_0.xlsx
BI-0153_selectivityData.xlsx
Reference molecule
For a recent review on FLAP inhibitors see Reference 2
Summary
BI 665915 demonstrates nanomolar FLAP binding potency and is a molecule suitable for testing biological hypotheses in vitro and also in vivo.
Supplementary data
2 D structure formats available
FLAP antagonist | BI 665915.png
FLAP antagonist | BI 665915.smiles
FLAP antagonist | BI 665915.sdf
Negative control | BI-0153.png
References
Synthesis, SAR, and Series Evolution of Novel Oxadiazole-Containing 5-Lipoxygenase Activating Protein Inhibitors: Discovery of 2-[4-(3-{(R)-1-[4-(2-Amino-pyrimidin-5-yl)-phenyl]-1-cyclopropyl-ethyl}-[1,2,4]oxadiazol-5-yl)-pyrazol-1-yl]-N,N-dimethyl-acetam
Takahashi H., Riether D., Bartolozzi A., Bosanac T., Berger V., Binetti R., Broadwater J., Chen Z., Crux R., De Lombaert S., Dave R., Dines J. A., Fadra-Khan T., Flegg A., Garrigou M., Hao M. H., Huber J., Hutzler J. M., Kerr S., Kotey A., Liu W., Lo H. Y., Loke P. L., Mahaney P. E., Morwick T. M., Napier S., Olague A., Pack E., Padyana A. K., Thomson D. S., Tye H., Wu L., Zindell R. M., Abeywardane A., Simpson T.
J. Med. Chem. 2015, 58, 1669-1690.
WO2013113799 A1
Lars Anders Bylock
How to cite opnMe?
When you plan a publication, please use the following acknowledgement:
BI 665915 was kindly provided by Boehringer Ingelheim via its open innovation platform opnMe, available at https://opnme.com.
Papers with our molecules. Published by you.
Related Molecules
