METHYL (1R,2R,4S)-2-[HEX-5-EN-1-YL(METHYL)CARBAMOYL]-4-({7-METHOXY-8-METHYL-2-[4-(PROPAN-2-YL)-1,3-THIAZOL-2-YL]QUINOLIN-4-YL}OXY)CYCLOPENTANECARBOXYLATE

Partition coefficient

Administrative data

Endpoint:

partition coefficient

Type of information:

experimental study

Adequacy of study:

key study

Study period:

15 March - 25 April 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 117 (Partition Coefficient (n-octanol / water), HPLC Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method A.8 (Partition Coefficient)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 830.7570 (Partition Coefficient, n-octanol / H2O, Estimation by Liquid Chromatography)

Deviations:

no

GLP compliance:

yes

Type of method:

HPLC method

Test material

Test material information

Constituent 1

Reference substance name:

methyl (1R,2R,4S)-2-[(hex-5-en-1-yl)(methyl)carbamoyl]-4-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)cyclopentane-1-carboxylate

EC Number:

922-147-8

Cas Number:

1042695-87-3

Molecular formula:

C32H41N3O5S

IUPAC Name:

methyl (1R,2R,4S)-2-[(hex-5-en-1-yl)(methyl)carbamoyl]-4-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)cyclopentane-1-carboxylate

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study reports): JNJ-39125593-AAA (T003019)
- Physical state: solid
- Appearance: white powder

Specific details on test material used for the study:

- Batch n°: M15FB2925
- Analytical purity: 99.5%
- Expiration date: 31 May 2017
- Storage condition: at room temperature protected from light

Study design

Analytical method:

high-performance liquid chromatography

photometric method

Results and discussion

Partition coefficient

Partition coefficient 1

Key result

Type:

log Pow

Partition coefficient:

> 7.2

pH:

4

Remarks on result:

other: the log Pow at pH 4 is unexpectedly high. Possibly there was increased retention due to interaction between the acetate buffer and the test item and the temperature was not specified

Partition coefficient 2

Key result

Type:

log Pow

Partition coefficient:

> 7.2

pH:

9

Remarks on result:

other: The temperature was not specified

Details on results:

Calculation method
The Pow of the test item was calculated to be 5.1E+6 (log Pow 6.7) using the Rekker calculation method.

Calculation of pKa values
pKa values between -1.6 and 6.4 were calculated for 3 basic groups in the molecule.
Based on these pKa values, it was decided to perform the test both at pH 4.0 (ionised form) and pH 9.0 (unionised form).

Main study at pH 4
The equation of the regression line was log k' = 0.306 log Pow - 0.748 (r=0.994, n=14). The retention time of the test item was outside the range of the references and therefore the log Pow is reported as > 7.2 (log Pow of the highest standard, benzo[ghi]perylene.

Main study at pH 9
The equation of the regression line was: log k’ = 0.311 log Pow – 0.922 (r=0.989, n=14). The retention time of the test item was outside the range of the references and therefore the log Pow is reported as > 7.2 (log Pow of the highest standard, benzo[ghi]perylene.

Considering the two calculated log Pow results for pH 4 and pH 9, which are 8.1 and 7.4 respectively, the result obtained for the log Pow of the ionised form at pH 4 is unexpectedly high. Though not observed frequently, a possible explanation is that there was increased retention due to interaction between the acetate buffer and the test item.

Any other information on results incl. tables

Results - pH 4:

Substance	tr,1 (min)	tr,2 (min)	Mean tr (min)	logPow
Formamide (t0 )	0.470	0.469	0.470
Benzylalcohol	0.619	0.602	0.611	1.1
Toluene	1.171	1.137	1.154	2.7
1,4 -Dichlorobenzene	1.492	1.450	1.471	3.4
1,2,4 -Trichlorobenzene	2.268	2.204	2.236	4.2
Dibenzyl	3.178	3.091	3.135	4.8
4,4’-DDT	8.033	7.840	7.937	6.5
Benzo[ghi]perylene	12.804	12.683	12.744	7.2
Test item	24.927	24.988	24.958	>7.2

Results - pH 9:

Substance	tr,1 (min)	tr,2 (min)	Mean tr (min)	logPow
Formamide (t0 )	0.493	0.493	0.493
Benzylalcohol	0.584	0.582	0.583	1.1
Toluene	1.032	1.027	1.030	2.7
1,4 -Dichlorobenzene	1.280	1.273	1.277	3.4
1,2,4 -Trichlorobenzene	1.897	1.884	1.891	4.2
Dibenzyl	2.405	2.385	2.395	4.8
4,4’-DDT	5.572	5.516	5.544	6.5
Benzo[ghi]perylene	10.311	10.172	10.242	7.2
Test item	12.175	12.180	12.178	>7.2

Applicant's summary and conclusion

Conclusions:

The HPLC method was applied for the determination of the partition coefficient (Pow) of JNJ-39125593-AAA (T003019).
The Pow value of the test item was 1.1E+8 at pH 4 (ionised form) and 2.4E+7 at pH 9 (unionised form).
The log Pow value of the test item was > 7.2 at pH 4 and at pH 9.