Comparison of Calculated Versus Measured Partition Coefficients of Some Phenyl ED-Glucopyranosides

KI HWAN KIM' AND YVONNE c. MARTIN Received April 14, 1986, from Abbott Laboratories, North Chicago, IL 60064. Accepted for publication May 13, 1986.

Abgtract 0 Experimentally determined octanol-water partition coeffi- cient values of substituted phenyl po-glucopyranosides are compared with the calculated values using the computer program CLOGP. The systematic deviation of the calculated values from the measured ones in this series suggests that caution is required when calculations are performed on Classes Of compounds where many Of the partition coeff icients have not been experimentally determined.

collected by the same authol% in the STARLIST data base of CLOGP.' We used a GcL' Program to search STARUX'' for reliable measured log P values of molecules that contain the -C(OR)CH(OH)CH(OH)- moiety. We augmented this list with other related compounds which were measured and reported by the same aUthors.6

Octanol-water partition coefficients (log P ) are one of the ~ o ~ o : most frequently used parameters in quantitative structurt+

activity relationship (QSAR) studies in drug research. It is

additive-constitutive principles.13 The computer program called CLOGP provides a convenient and state of the art means of calculating the partition coefficients of various organic compounds.

In the course of our study of some polyhydroxy pyranose compounds, the octanol-water partition coefficients of some compounds were experimentally determined. It was noticed that the measured values do not agree well with those calculated by CLOGP the calculated values were much lower than the measured ones. For this reason, we compared the calculated values of some polyhydroxy pyranose com- pounds against the "reliable", measured ones, that had been Table CComparlron of Calculated and MearureJd log P Valuea of &P.Olucopyranorlder

X

well established that these values can be estimated using OH OH

1

Table I lists the phenyl pglucopyranoside (1) analogues included in this study, their measured log P values, their calculated log P values from CLOGP, and their complete SMILES (simplified molecular input line entry system).' The measurements were performed in one laboratory,6 except for the 2-methoxy (71, and 3,5-di-tert-butyl (16) compounds. The source of the log P values of these two compounds are not clear to us, but they are found in the STARLIST.

Although the calculated log P values of four compounds (1, 3,16, and 17) are reasonable, that is the deviation is c0.4, all the calculated log P values in Table I are lower than the

No. Substituents CLOGP' D E V ~ log PC S M I L E S ~

1 3,5-di-tert-Butyl 2.61 1 -0.12 2.73 CC(C)(C)cl cc(cc(c1 )c(c)(c)c)oc2oc(co)c(o)c(o)c2o 2 4-teRButyl 0.635 -0.55 1.18 CC(C)(C)cl ccc(cc1 )oc2oc(co)c(o)c(o)c2o 3 2-lsopropyl, 5-Methyl 0.885 -0.19 1.07 CC(C)Cl ccc(cc1 oc2oc(co)c(o)c(o)c2o)c 4 3-Ethyl -0.163 -0.47 0.31 Cccl cccc(c1 )oc2oc(co)c(o)c(o)c2o 5 4-Methoxy - 1.252 -0.52 -0.73 Cocl ccc(ccl)oc2oc(co)c(o)c(o)c2o 6 3-Methoxy - 1.252 -0.73 -0.52 Cocl cccc(c1 )oc2oc(co)c(o)c(o)c2o 7 2-Methoxy -1.812 -0.77 -1.04 Cocl cccccl oc2oc(co)c(o)c(o)c2o 8 4-l& -0.078 -0.83 0.75 OCC20C(ocl ccc(ccl)l)c(o)c(o)c2o

10 4-H ydroxy - 1.828 -0.48 -1.35 occ2oc(ocl ccc(ccl)o)c(o)c(o)c2o

12 H - 1.341 -0.63 -0.71 occ2oc(ocl ccccCl )c(o)c(o)c2o

14 2-Hydroxymethyl -2.379 -1.16 -1.22 occ2oc(ocl cccccl co)c(o)c(o)c2o 15 2,3-CH=CHCH=CH- -0.167 -0.93 0.76 occ3oc(oc2cccl cccccl c2)c(o)c(o)c3o 16 3-tert-Butyl 0.635 -0.38 1.01 CC(C)(C)cl cccc(cl)OC20C(CO)C(O)C(O)C20 17 3,5-Dimethyl -0.043 -0.30 0.26 ccl cc(cc(c1 )oc2oc(co)c(o)c(o)c2o)c 18 4-Chloro -0.488 -0.75 0.26 occ2oc(ocl ccc(cc1 )cgc(o)c(o)c2o

9 4-Nitro - 1.298 -0.86 -0.44 OCC2OC(Ocl ccc(cc1 )N(=O)=O)C(O)C(O)CPO

11 3-Trifluoromethyl -0.213 -0.70 0.49 OCC20C(Ocl ccCc(cl)C(F)(F)F)C(O)C(O)C20

13 3-Nitro - 1.298 -0.79 -0.51 OCC2OC( Ocl cccc(c 1 ) N (=O)=O)C( O)C( O)C20

AVERAGE DEV of 19 compounds (1-18): -0.620

19 2-Methyl 20 2-lodo 21 2-Nitro 22 2-Amino 23 3-Methyl 24 3-lsopropyl 25 4-Methyl 26 4-Amino

-0.692 -0.358 - 1 578 -2.384 -0.692

0.236 -0.692 -2.384

-0.53 -0.63 -0.80 -1.15 -0.49 -0.41 -0.53

0.29

-0.16 0.27

-0.78 -1.23 -0.20

0.65 -0.16 -2.67

CCl cccccl oc2oc(co)c(o)c(o)c2o Icl Cccccl oc2oc(co)c(o)c(o)c2o O=N(=O)cl cccccl OC20C(CO)C(O)C(O)C20 Ncl cccccl OC20C(CO)C(O)C(O)C20 cl c(C)ccccl oc2oc(co)c(o)c(o)c2o cl c(C(C)(C))ccccl oc2oc(co)c(o)c(o)c2o cl cc(C)cccl oc2oc(co)c(o)c(o)c2o cl cc(N)cccl OC20C(CO)C(O)C(O)C20

AVERAGE DEV of 25 compounds [l-25 (19-26 not in the STARLIST)]: -0.628

*CLOGP = Calculated log P values using CLOGP program. bDEV = CLOGP - log P. cLog P = measured log P values from STARLIST of CLOGP program and ref. 5. dSMILES = Simplified molecular input line entry system of CLOGP program.

0022-3549/86/0700-0637$0 l.OO/O Q 1986, American Pharmaceutical Association

Journal of Pharmaceutical Sciences / 637 Vol. 75, No. 7, July 1986

measured ones. This was also the direction of difference of the measured compared with the calculated log P values of our compounds.

Among the 26 compounds, 18 had been included in the supposedly more reliable STARLIST data base. The average deviation of the calculated values of these 18 compounds is -0.620 f 0.269; the average deviation of the compounds that are not in the STARLIST is -0.649 f 0.253; and the average deviation of all 25 phenyl pbglucopyranoside compounds is -0.628 f 0.260. The essentially equal deviation in both sets of compounds and the correlation between the measured values and log P values of phenol or phenoxyacetic acid analogues6 suggest that the compounds that are not included in the STARLIST do not behave much differently from the other analogues. The low standard deviation of these values also suggeste that there is a constant difference between the calculated and measured partition coefficient values in this eeries. The measured log P value of 26 is considered as an outlier (see Tables I1 and III).6

Although a systematic deviation of the experimental error cannot be excluded as a possible explanation for this system- atic deviation, it does not appear to be the case because we observed a similar trend in the partition coefficient values of our compounds, and two analogues were measured in differ- ent laboratories. In a related series, we noticed a large difference between the measured and the calculated values of five hydroxy furanose analogues listed in STARLIST. How- ever, their structures were more diverse, and the series is so small that further analysis was not fruitful. Benzyl PD- glucopyranoside and cyclohexyl Pbglucopyranosideu are two other examples.

The purpose of this report is to offer a warning to users of CLOGP about the systematic deviation that we observed with phenyl pbglucopyranoside compounds. We suggest that it is prudent to establish the validity of calculated log P values for the compounds of interest by comparing the observed and calculated values for structurally similar com- pounds. The present results once again remind us that good measured values are always preferred over calculated ones. Finally, we stress that it is not our intention at all to devalue the CLOGP program. In fact, we are quite satisfied with its calculations in most cases,7 and still strongly recommend use of this program whenever calculation is justified over experi- mental measurement.

Table ICComparlson of Log P Values o? Porklonal I6omerr

No.' Substituents CLOGPb Del 1' L o g P" Del 2'

2 16

5 6 7

8 20

9 13 21

25 23 19

26 22

4-terl-Butyl 3-tert-Butyl

4-Methoxy 3-Methoxy 2-Methoxy

4-lodo 2-lodo

4-Nitro 3-Nitro 2-Nitro

4-Methyl 3-Methyl 2-Methyl

4-Amino 2-Amino

0.635 0.635

- 1.252 - 1.252 -1.812

-0.078 -0.358

- 1.298 -1.298 - 1.578

-0.692 -0.692 -0.692

-2.384 -2.384

- 0.00

- 0.00

-0.56

- -0.28

- 0.00

-0.28

- 0.00 0.00

- 0.00

1.18 1.01

-0.73 -0.52 -1.04

0.75 0.27

-0.44 -0.51 -0.78

-0.16 -0.20 -0.16

-2.67 -1.23

- 0.17

0.21 -0.31

- 0.48

- -0.07 -0.34

- -0.04 0.00

- 1.44

'See Table I. bCalculated using CLOGP program. 'Del 1 = differ- ence in CLOGP between 4-substituents and 2- or 3-substituents. dMeasured log P values. 'Del 2 = difference in log P between 4- substituents and 2- or 3-substituents.

Table llLCalcul8td Log P Valuer Used In Equatlonr 1-4

Obs Substituents L o g P CLOGPOb CLOGPP'

1 3,5-di-tert-Butyl 2.73 5.427 5.366 2 4-tert-Butyl 1.18 3.451 3.390 3 2-lsopropyl, 5-Methyl 1.07 3.701 3.640

5 4-Methoxy -0.73 1.574 1.333 6 3-Methoxy -0.52 1.574 1.333 7 2-Methoxy -1.04 1.294 1.333

4 3-Ethyl 0.31 2.653 2.592

8 4-lodo 0.75 2.895 2.537 9 4-Nitro -0.44 1.854 1.157

10 4-Hydroxy -1.35 0.808 0.747 11 3-Trifluoromethyl 0.49 2.877 2.297 12 H -0.71 1.475 1.414 13 3-Nitro -0.51 1.854 1.157 14 2-Hydroxymethyl -1.22 0.437 0.376 15 2,3-CH=CHCH=CH- 0.76 2.649 2.588 16 3-lerl-Butyl 1.01 3.451 3.390 17 3,5-Dimethyl 0.26 2.773 2.712 18 4-Chloro 0.26 2.485 2.127

20 2-lodo 0.27 2.61 5 2.537 21 2-Nitro -0.78 1.854 0.877 22 2-Amino -1.23 0.648 0.187

19 2-Methyl -0.16 2.124 2.063

23 3-Methyl -0.20 2.124 2.063 24 3-lsopropyl 0.65 3.052 2.991 25 4-Methyl -0.16 2.124 2.063 26 4-Amino -2.67 0.248 0.203

"See Table I. bCLOGPO = calculated log P of phenol analogues. 'CLOGPP = calculated log P of phenoxyacetic acid analogues.

References and Notes 1. F 'ita, T.; Iwaea, J.; Hansch, C. J . Amer. Chem. Soc. 1964,86,

2. Hankh. C.: Leo. A. "Substituent Constanta for Correlation 5 3 5

- . - . . . - . . . - ._ .. .. Analysis in 'Chemistry and Biology"; Wiley. New York, 1979.

3. Leo A. J. Chem. Soc., Perkin Tmns. ZZ 1983, 825. 4. CL6GP program, MedChem Software Manual, V. 3.33, March

1985, Medicinal Chemistry Project, Pomona College, Clammont, CA.

5. Poretz, R. D.; Goldstein, I. J. Arch. Biochern. Biophys. 1968,125, 1034.

6. Compound 26 is the only compound that has a positive deviation, and also most closely agrees with the measured value. However, baaed on the comparison of the partition coefficienta of 2-amino and 4-amino compounds with other positional isomers (see Table II), as well as the correlation between the measured log P values of all phen 1 pwglucopyranoside com unds and log P values calculated &r phenol (eqs. 1 and 3) or prenoxyacetic acid (eqs. 2 and 4) analogues (see Table 111) using the CLOGP program, the measured partition coefficient value of 26 is coneidered a~ an outlier. In eqs. 1 and 2, the calculated lo P values of 26 deviate from the measured value by 0.92 and 1%, respectively.

log P (glucopyranoside) = 0.86 CLOGP(pheno1) - 1.96

log P (glucopyranoside) = 0.79 CLOGP(phenoxyacetic

n = 25, s = 0.18, r = 0.98 (1)

acid) - 1.62 n = 25, s = 0.23, r = 0.97 (2)

When only the 18 compounds in the STARLIST were used, eqs. 3 and 4 were obtained, which is essentially the same as eqs. 1 and 2.

log P (glucopyranoeide) = 0.86 CLOGP(pheno1) - 1.94

log P (glucopyranoside) = 0.82 CLOGP(phenoxyacetic

n = 18, s = 0.19 r = 0.99 (3)

acid) - 1.67 n = 18, s = 0.25, r = 0.97 (4)

7. Kim, K. H.; Martin, Y. C. in "QSAR in Design of Bioactive Com unds", Proceedings of the 1st Telesym sium on Medici- nal Gemistry; J. R. Prous Publishers: Barcecna, Spain, 1984, pp 61 and 447.

630 /Journal of Pharmaceutical Sciences Vol. 75, No. 7, July 1986