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[ CAS No. 22246-12-4 ] {[proInfo.proName]}

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Chemical Structure| 22246-12-4
Chemical Structure| 22246-12-4
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Product Citations

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Elizabeth Bester ; An′el Petzer ; Jacobus P. Petzer DOI: PubMed ID:

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).

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).

Keywords: coumarin ; dihydroisoquinolinone ; D-amino acid oxidase ; monoamine oxidase ; inhibition ; schizophrenia ; depression ; Parkinson’s disease

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Product Details of [ 22246-12-4 ]

CAS No. :22246-12-4 MDL No. :MFCD04114865
Formula : C10H11NO2 Boiling Point : -
Linear Structure Formula :- InChI Key :WLQWIZAWNPYMBR-UHFFFAOYSA-N
M.W : 177.20 Pubchem ID :10607392
Synonyms :
Chemical Name :6-Methoxy-3,4-dihydroisoquinolin-1(2H)-one

Calculated chemistry of [ 22246-12-4 ]      Expand+

Physicochemical Properties

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 : 38.33 ?2

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.53 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.78
Log Po/w (XLOGP3) : 1.2
Log Po/w (WLOGP) : 0.6
Log Po/w (MLOGP) : 1.14
Log Po/w (SILICOS-IT) : 2.07
Consensus Log Po/w : 1.36

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.97
Solubility : 1.9 mg/ml ; 0.0107 mol/l
Class : Very soluble
Log S (Ali) : -1.6
Solubility : 4.44 mg/ml ; 0.025 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.29
Solubility : 0.0903 mg/ml ; 0.000509 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.55

Safety of [ 22246-12-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 22246-12-4 ]

* 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.

  • Downstream synthetic route of [ 22246-12-4 ]

[ 22246-12-4 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 2051-99-2 ]
  • [ 22246-12-4 ]
  • 2-(4-isobutylphenyl)-6-methoxy-3.4-dihydroisoquinolin-1(2H)-one [ No CAS ]
YieldReaction ConditionsOperation 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.
  • 2
  • [ 20651-67-6 ]
  • [ 22246-12-4 ]
  • 2-(4-butylphenyl)-6-methoxy-3,4-dihydroisoquinolin-1(2H)-one [ No CAS ]
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