Structure of 1254058-34-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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Hiroto Kataoka ; Tetsuya Saita ; Asuki Oka ; Momoka Yamada ; Masashi Shin ;
Abstract: Brigatinib and gilteritinib are oral tyrosine kinase inhibitors (TKIs). We aimed to develop a simple and sensitive indirect competitive enzyme-linked immunosorbent assay (ELISA) to quantify brigatinib and gilteritinib in various biological matrices. Antiserum against these TKIs was obtained from mice by using 3-methoxy-4-(-4-(4-methylpiperazin-1-yl) piperidin-1-yl) aniline as a hapten, which has a common substructure with these TKIs. The generated antibody was used to develop an indirect competitive ELISA for these TKIs in human serum. The lower limit of quantification of brigatinib and gilteritinib in human serum was 6.2 and 6.8 ng/mL, respectively. The developed ELISA was used to examine the pharmacokinetics of these TKIs after oral administration in mice and rats. This ELISA is expected to be a valuable tool in pharmacokinetic studies of these TKIs.
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Keywords: brigatinib ; gilteritinib ; enzyme-linked immunosorbent assay ; tyrosine kinase inhibitor
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CAS No. : | 1254058-34-8 |
Formula : | C17H28N4O |
M.W : | 304.43 |
SMILES Code : | NC1=CC=C(N2CCC(N3CCN(C)CC3)CC2)C(OC)=C1 |
MDL No. : | MFCD28129029 |
InChI Key : | JHPDGTZPYTWLTG-UHFFFAOYSA-N |
Pubchem ID : | 68014035 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 22 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.65 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 102.33 |
TPSA ? Topological Polar Surface Area: Calculated from |
44.97 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.92 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.74 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.36 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.27 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.93 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.44 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.83 |
Solubility | 0.453 mg/ml ; 0.00149 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.3 |
Solubility | 1.52 mg/ml ; 0.005 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.82 |
Solubility | 0.465 mg/ml ; 0.00153 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
Yes |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.92 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
1.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.93 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17 mg | Example 10 To a mixture of 1-(bromomethyl)-2,6-difluorobenzene (14 mg), <strong>[4983-28-2]2-chloro-5-hydroxypyrimidine</strong> (9.1 mg), and N,N-dimethylformamide (1 mL), potassium carbonate (16 mg) was added followed by stirring at room temperature overnight. To the reaction mixture, water was added followed by extraction with chloroform. An organic layer obtained was concentrated under reduced pressure. To the resulting residue, a mixture of 3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (30 mg), cesium carbonate (65 mg), palladium acetate-X-Phos (Pd:P=1:2) ChemDose (trademark) tablet, and tert-butyl alcohol (0.5 mL) was added followed by stirring at 120° C. overnight under a nitrogen atmosphere. To the reaction mixture, water was added followed by extraction with chloroform. An organic layer obtained was concentrated under reduced pressure. The resulting residue was purified by HPLC (0.1percent aqueous formic acid solution/methanol) to give 5-[(2,6-difluorobenzyl)oxy]-N-{3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidin-2-amine (17 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 110℃; for 19h; | A mixture of <strong>[313340-08-8]3,5-dichloro-6-ethylpyrazine-2-carboxamide</strong> (3a, 90 mg, 0.409 mmol), 3-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (124 mg, 0.407 mmol), DIPEA (71 muL, 0.408 mmol) and 1,4-dioxane (3.6 mL) was stirred at 110 C for 19 h. After the mixture was cooled, water was added, and the resulting slurry was extracted with EtOAc. The organic layer was dried over Na2SO4, andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (CHCl3/MeOH) to give 11 (110 mg, 55%) as an ochersolid. 1H NMR (CDCl3): delta 1.28 (3H, t, J=7.4 Hz), 1.72-1.99 (4H, m),2.29 (3H, s), 2.34-2.78 (11H, m), 2.85 (2H, q, J=7.5 Hz), 3.44-3.59(2H, m), 3.89 (3H, s), 5.38-5.57 (1H, m), 6.90 (1H, d, J=8.4 Hz),7.08-7.19 (1H, m), 7.32-7.41 (1H, m), 7.62-7.80 (1H, m), 10.66 (1H,s); MS (ESI) m/z [M+H]+ 488, 490. |
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