2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Data source

Reference

Reference 1

Reference Type:

publication

Title:

In silicon models for the prediction of dose-dependent human hepatotoxicity

Author:

Ailan Cheng, Steven L. Dixon

Year:

2003

Bibliographic source:

Journal of Computer-Aided Molecular Design

Reference 2

Reference Type:

publication

Title:

Investigation of classification methods for the prediction of activity in diverse chemical libraries

Author:

Steven L. Dixon, Hugo O. Villar

Year:

1999

Bibliographic source:

Journal of Computer-Aided Molecular Design

Reference 3

Reference Type:

publication

Title:

Predicting the Genotoxicity of Secondary and Aromatic Amines Using Data Subsetting To Generate a Model Ensemble

Author:

Brian E. Mattioni, Gregory W. Kauffman, Peter C. Jurs

Year:

2003

Bibliographic source:

Journal of Chemical Information and Computer Science

Reference 4

Reference Type:

publication

Title:

Prediction of Aqueous Solubility of a Diverse Set of Compounds Using Quantitative Structure-Property Relationships

Author:

Ailan Cheng, Kenneth M.Merz, Jr.

Year:

2003

Bibliographic source:

Journal of Medicinal Chemistry

Reference 5

Reference Type:

publication

Title:

One-Dimensional Molecular Representations and Similarity Calculations: Methodology and Validation

Author:

Steven L. Dixon, Kenneth M. Merz, Jr.

Year:

2001

Bibliographic source:

Journal of Medicinal Chemistry

Reference 6

Reference Type:

publication

Title:

Prediction of Drug Absorption Using Multivariate Statistics

Author:

William J. Egan, Kenneth M. Merz, Jr., John J.Baldwin

Year:

2000

Bibliographic source:

Journal of Medicinal Chemistry

Reference 7

Reference Type:

publication

Title:

Use of Robust Classification Techniques for the Prediction of Human Cytochrome P450 2D6 Inhibition

Author:

Roberta G. Susnow, Steven L. Dixon

Year:

2003

Bibliographic source:

Journal of Chemistry Information and Computer Science

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: REACH guidance on QSARs R.7c, May/July 2008

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one

EC Number:

400-600-6

EC Name:

2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one

Cas Number:

71868-10-5

Molecular formula:

C15H21NO2S

IUPAC Name:

2-methyl-1-[4-(methylsulfanyl)phenyl]-2-(morpholin-4-yl)propan-1-one

Details on test material:

CC(N1CCOCC1)(C)C(C2=CC=C(SC)C=C2)=O
Both descriptors of AlogP value of 2.601 and PSA value of 29.583 were used for the ADME descriptors model.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The substance has a good human intestine absorption or respiration tract absorption.
The physico-chemical properties of the substance are listed as follows: water solubility is 17.9mg/L, logP is 3.09, MW is 279.40g/mol, and its particle size distribution is from approximately 0.3 microm to 125 microm, Mass Median Diameter is 22.1microm. It is concluded from the above that the substance has good human intestine absorption or respiration tract absorption.

Details on distribution in tissues:

The substance has a lower volume of distribution in the human body with the plasma protein binding more than 95%, which has less capability of distributing in tissues in body.

Transfer into organs

Test no.:

#1

Transfer type:

blood/brain barrier

Observation:

distinct transfer

Details on excretion:

This compound may be favourable for urinary excretion due to its low molecular weight (below 300), good water solubility.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

The substance is unlikely to cause dose-dependent liver injuries and may not be metabolized in liver.

Any other information on results incl. tables

validity of model:

1. Defined endpoint: Toxicokinetics

2. Unambiguous algorithm:

(1)Absorption: Pattern recognition model

(2)Aqueous Solubility: Multiple linear regressions and genetic algorithms were used to develop the models. 

log(Sw)=-0.7325*<AlogP98>-0.4985*<HBD>*<HBA>-0.5172*<Zagreb>-0.0780*<S_aaaC>+0.1596*<Rotlbonds>+ 0.2057*<HBD>+0.1834*<S_sOH>+ 0.2539*<Wiener>

(3)Blood Brain Barrier: A regression model to predict logBB values was derived from a training set of 102 compounds and a test set of 86 compounds.

(4)Plasma Protein Binding: Predictions are based on the similarity between the candidate molecule and two sets of marker molecules

(5)CYP2D6 Binding: an ensemble recursive partitioning model

(6) Hepatotoxicity: an ensemble recursive partitioning model.

3. Applicability domain: For small molecules, particularly the MW<500.

4. Statistics characteristics:

(1)Absorption:The correct predictivity about the external validation are as follows: (1)Physician’s Desk Reference (PDR): 87.4% of 438 orally delivered compounds; (2) World Drug Index: 82.9% of 8504 with USAN or INN; (3) Comprehensive Medicinal Chemistry: 83.5% of 5836 filtered by class; (4) Pharmacopeia’s Caco-2 data (446 compounds with low, moderate, and high permeability (i.e., P_app), used in many PCOP Labs collaborative projects): a) Moderate/High Papp: 91.5% of compounds lie within 99% ellipse; b) Low Papp: 20.6% of compounds lie within 95% ellipse.

(2)Aqueous Solubility:The test set consisted of 34 compounds, and the regression statistics are R²=0.88 and standard deviation=0.79. A validation test consisting of 1615 compounds from the PDR, Comprehensive Medicinal Chemistry database (CMC), and other sources was also performed. Results yield and overall RMSE (SD) of 1.0.

(3)Blood Brain Barrier: Further testing against a collection of 124 compounds with known logBB values yielded an R²=0.889 and SD=0.306.

(4)Plasma Protein Binding: N/A

(5)CYP2D6 Binding:True Positive = 10/10, Sensitivity = 100%; True Negative = 31/41, Specificity = 76%; Total accuracy=41/51, Q=80%.

(6)Hepatotoxicity: True Positive = 16/23, Sensitivity = 70%; True Negative = 28/31, Specificity = 90%; Total accuracy=44/54, Q=81%. t hepatotoxicity.

5. Mechanistic interpretation: These admet descriptors model maily related the descriptors AlogP and polar surface area.

Applicant's summary and conclusion

Conclusions:

The substance 2-methyl-1-(4-methylthiophenyl)-2-morpholinopropan-1-one was predicted to has no bioaccumulation potential. The prediction of submodels are listed as follows:
The HIA model indicate that the substance has a good human intestine absorption. The model of plasma protein binding and another blood brain barrier indicate that the substance has a lower volume of distribution in the human body and can across blood-brain barrier and access to central nervous system. The substance is unlikely to cause dose-dependent liver injuries and may not be metabolized in liver as a result of the hepatotoxicity model and CYP2D6 inhibitor model. Because of its lower molecular weight and good water solubility, the substance is favourable for urinary excretion.