FLAP antagonist | BI 665915
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Highlights
5‑Lipoxygenase Activating Protein (FLAP) is an important protein in the Leukotriene pathway. BI 665915 demonstrates excellent FLAP binding potency with an IC50 of below 10 nM and potent inhibition of LTB4 synthesis in human whole blood with an IC50 of below 100 nM. It is an excellent molecule for testing biological hypotheses in vitro and also in vivo.1 A favourable cross-species drug metabolism and DMPK profile and good selectivity make it an excellent molecule for testing biological hypotheses in vitro and in vivo. The compound is also active in mice which differentiates it from related compounds as highlighted in a recent review by D. Pettersen et al.2
With BI-0153 we also offer a structurally similar molecule which can be used as negative control for in vitro experiments due to significant weaker potency (670 nM).
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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 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 iv 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 iv 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 = iv, 1 mg/kg; dosing vehicle, 70% PEG; po, 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 24 h) per iv or po 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
Panlabs® External screen covering 68 targets @ 10 µM
Cerep® External screen covering 137 targets @ 20 µM
Selectivity data available
|
Probe name |
BI 665915 |
|
Cerep® |
Yes |
|
Eurofins-Panlabs® |
Yes |
|
Invitrogen® |
Yes |
|
DiscoverX® |
No |
|
Dundee |
No |
reference molecules
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
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.
Recent advances for FLAP inhibitors
Pettersen D, Davidsson Ö., Whatling C.
Bioorg. Med. Chem. Lett. 2015, 25, 2607-2612.
Funk Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology
Colin D.
Science 2001, 294, 1791-1875.
Crystal Structure of Inhibitor-Bound Human 5-Lipoxygenase–Activating Protein
Ferguson A. D., McKeever B. M., Xu S., Wisniewski D., Miller D. K., Yamin T. T., Spencer R. H., Chu L., Ujjainwalla F., Cunningham B. R., Evans J. F., Becker J. W.
Science 2007, 317, 510-512.
Treatment of Asthma with Drugs Modifying the Leukotriene Pathway
Drazen J. M., Israel E., O'Byrne P. M.
Science 2007, 317, 510-512.
The 5 lipoxygenase system in the vasculature: Emerging role in health and disease
Osher E., Weisinger G., Limor R., Tordjman K., Stern N.
Mol. Cell. Endcrinol. 2006, 252, 201−206.
WO2013113799 A1
Lars Anders Bylock
