Structure of 22246-12-4
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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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Coumarin derivatives as inhibitors of d-amino acid oxidase and monoamine oxidase
Elizabeth Bester ; An´el Petzer ; Jacobus P. Petzer ;
Abstract: d-Amino acid oxidase (DAAO) oxidises d-amino acids to ultimately produce the corresponding α-keto acids. The DAAO substrate, d-serine, is a co-agonist at NMDA receptors, while NMDA receptor hypo-function has been implicated in the pathophysiology of schizophrenia. Through the modulation of d-serine levels, the inhibition of DAAO represents a strategy to increase NMDA receptor function, and thus a potential treatment for schizophrenia. Literature reports that 3-hydroxycoumarin is a potent inhibitor of DAAO and represents an ideal lead for the development of novel DAAO inhibitors. Based on this, the present study investigated DAAO inhibition by a series of synthetic and commercially available coumarin derivatives. Due to structural similarity to coumarin, a synthetic series of 3,4-dihydroisoquinolin-1(2H)-one derivatives has also been included in this study. The results show that among 37 compound evaluated, four inhibit porcine kidney DAAO with IC50 < 10 µM. The most potent inhibitors are 3,7-dihydroxycoumarin and 6,7-dihydroxycoumarin with an IC50 values of 0.167 and 0.224 µM, respectively. These values are an improvement on that of the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC50 = 1.88 µM). Coumarin compounds are also known to inhibit the monoamine oxidase (MAO) enzymes, which are well established targets for the treatment of depression and Parkinson’s disease. As DAAO and MAO are flavoenzymes, off-target inhibition may occur. The series were thus evaluated as potential MAO inhibitors, and a number of high potency inhibitors were identified. Seven compounds inhibit the recombinant human MAOs with IC50 < 0.1 µM, with the most potent MAO-A and MAO-B inhibitors exhibiting IC50 values of 0.033 and 0.012 µM, respectively. This is significantly more potent than the reference inhibitors, curcumin, isatin and toloxatone. This study concludes that active DAAO and MAO inhibitors may serve as novel leads for the design of compounds that may find future application in the treatment of neuropsychiatric (e.g. schizophrenia, depression) and neurodegenerative disorders (e.g. Parkinson’s disease).
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Keywords: Coumarin ; D-amino acid oxidase ; Monoamine oxidase ; Schizophrenia ; Depression ; Parkinson’s disease
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Elizabeth Bester ;
Abstract: Schizophrenia is a mental disorder with many clinical and therapeutic challenges. Current therapy is based on outdated pathological theories while most antipschycotic drugs have a significant side effect profile. New theories to explain the pathology of schizophrenia are being developed and novel drugs that act as improved antipsychotics are needed. D-Amino acid oxidase (DAAO) oxidises D-amino acids to ultimately produce the corresponding α-keto acids. D-Serine is an example of a substrate of DAAO and is a co agonist at the NMDA receptor. NMDA receptor hypo function has been implicated in the pathophysiology of schizophrenia. A strategy to improve NMDA receptor function is the inhibition of DAAO, and thereby to increase central D-serine levels. This approach serves as a potential treatment for schizophrenia. The small molecule, 3-hydroxycoumarin, is a potent inhibitor of DAAO, and represents an ideal lead for the development of novel DAAO inhibitors. Based on this, the present study investigated the DAAO inhibition potencies of series of synthetic and commercially available coumarin derivatives. Due to structural similarity to coumarin, a synthetic series of 3,4-dihydroisoquinolin-1(2H)-one derivatives was also included in this study. Among the 37 compounds that were evaluated, four inhibited porcine kidney DAAO with IC50 < 10 μM. The most potent inhibitor was 6,7-dihydroxycoumarin with an IC50 value of 0.224 μM. These values are significantly more potent than the reference DAAO inhibitor, 3-methylpyrazole-5-carboxylic acid (IC50 = 1.88 μM). Coumarin compounds are also known to be inhibitors of the monoamine oxidase (MAO) enzymes, which are well established targets for the treatment of depression and Parkinson’s disease. The series were thus evaluated as potential MAO inhibitors, and a number of high potency inhibitors were identified. Seven compounds inhibited the recombinant human MAOs with IC50 < 0.1 μM, with the most potent MAO-A and MAO-B inhibitors exhibiting IC50 values of 0.033 and 0.012 μM, respectively. These compounds are significantly more potent that the reference inhibitor, curcumin, with IC50 values of 5.02 and 2.56 μM for the inhibition of MAO-A and MAO-B, respectively. This study concludes that active DAAO and MAO inhibitors may serve as novel leads for the design of compounds that may find future application in the treatment of neuropsychiatric (e.g. schizophrenia, depression) and neurodegenerative disorders (e.g. Parkinson’s disease).
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Keywords: coumarin ; dihydroisoquinolinone ; D-amino acid oxidase ; monoamine oxidase ; inhibition ; schizophrenia ; depression ; Parkinson’s disease
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CAS No. : | 22246-12-4 |
Formula : | C10H11NO2 |
M.W : | 177.20 |
SMILES Code : | O=C1NCCC2=C1C=CC(OC)=C2 |
MDL No. : | MFCD04114865 |
InChI Key : | WLQWIZAWNPYMBR-UHFFFAOYSA-N |
Pubchem ID : | 10607392 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.3 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 52.7 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.33 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.78 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.2 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.6 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.14 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.07 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.36 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.97 |
Solubility | 1.9 mg/ml ; 0.0107 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.6 |
Solubility | 4.44 mg/ml ; 0.025 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.29 |
Solubility | 0.0903 mg/ml ; 0.000509 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 |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
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) |
No |
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 |
-6.53 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 |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.55 |
* 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 |
---|---|---|
43.5% | With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 24h;Inert atmosphere; | Intermediate A6 2-(4-isobutylphenyl)-6-methoxy-3.4-dihvdroisoquinolin-l(2H)-one vial, 6-methoxy-3,4-dihydroisoquinolin-l(2H)-one (0.25 g, 1.411 mmol) was dissolved in N-dimethylformamide (2.82 ml). To this was added l-bromo-4-isobutylbenzene (0.451 g, 2.116 mmol) and potassium carbonate (0.390 g, 2.82 mmol). The reaction mixture was flushed with nitrogen, charged with copper(I) iodide (0.161 g, 0.847 mmol) and heated to 150 C for 24 h. The reaction mixture was cooled to room temperature, quenched with water and extracted three times with dichloromethane. The organic layers were combined, passed through a phase separator and concentrated. The crude material was purified via silica gel chromatography using 0-75% ethyl acetate in heptanes to afford the desired product (190 mg, 0.614 mmol, 43.5 % yield) as a light orange solid. NMR (400 MHz, Chloroform-d) delta 8.12 (d, J = 8.7 Hz, 1H), 7.32 - 7.27 (m, 2H), 7.24 - 7.15 (m, 2H), 6.89 (dd, J = 8.7, 2.6 Hz, 1H), 6.77 - 6.65 (m, 1H), 3.96 (dd, J = 7.0, 6.0 Hz, 2H), 3.86 (s, 3H), 3.09 (t, J = 6.4 Hz, 2H), 2.50 (d, J = 7.1 Hz, 2H), 1.90 (dh, J = 13.5, 6.8 Hz, 1H), 0.94 (d, J = 6.6 Hz, 6H). LC MS (m/z, MH+): 310.4. |
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