Computational models to predict blood-brain barrier permeation and CNS activity

Journal of Computer-Aided Molecular Design

Volumn 17, Issue 10, 2003, Pages 643-664

  Subramanian, Govindan ^a,b   Kitchen, Douglas B ^a  

^a ALBANY MOLECULAR RESEARCH INC   (United States)

^b Transtech Pharma   (United States)

Author keywords

Blood brain barrier; CNS penetrations; G PLS regression; logBB; QSAR

Indexed keywords

BLOOD; CLASSIFICATION (OF INFORMATION); COMPUTATIONAL CHEMISTRY; FORECASTING; LEAST SQUARES APPROXIMATIONS; MOLECULES;

BEST MODEL; BLOOD-BRAIN BARRIER; CNS PENETRATION; COMPUTATIONAL MODELLING; EXPERIMENTAL VALUES; GENETIC PARTIAL LEAST SQUARE REGRESSION; LOGARITHM OF BLOOD-BRAIN PARTITIONING; PARTIAL LEAST SQUARE REGRESSION; QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP; QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP MODELING;

BRAIN;

2 AMINO 4 METHYL 5 PHOSPHONO 3 PENTENOIC ACID ETHYL ESTER; 8 CHLORO 2,3,4,5 TETRAHYDRO 3 METHYL 5 PHENYL 1H 3 BENZAZEPIN 7 OL HYDROGEN MALEATE; ABECARNIL; AMANTADINE; APOMORPHINE; BACLOFEN; CLOBAZAM; CLOMIPRAMINE; CLOZAPINE; CYCLOBARBITAL; DOPAMINE; DOXEPIN; FLUMAZENIL; FLUNITRAZEPAM; FLURAZEPAM; IFENPRODIL; KETAMINE; LAMOTRIGINE; METHADONE; MORPHINE; NITRAZEPAM; OXCARBAZEPINE; PHENOBARBITAL; PROGABIDE; RACLOPRIDE; SULPIRIDE; TIAGABINE; TRIAZOLAM; UNINDEXED DRUG; ZIMELDINE;

ACCURACY; BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; CHEMICAL STRUCTURE; CLASSIFICATION; COMPUTER MODEL; COMPUTER SIMULATION; CONTROLLED STUDY; CORRELATION ANALYSIS; DATA BASE; DRUG ACTIVITY; DRUG PENETRATION; DRUG RESEARCH; LINEAR REGRESSION ANALYSIS; MULTIVARIATE ANALYSIS; PREDICTION; PRIORITY JOURNAL; QUALITY CONTROL; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; STATISTICAL ANALYSIS;

EID: 1542503699     PISSN: 0920654X     EISSN: None     Source Type: Journal    
DOI: 10.1023/B:JCAM.0000017372.32162.37     Document Type: Review

References (63)

1. Gallop, M.A., Barrett, R.W., Dower, W.J., Fodor, S.P.A. and Gordon, E.M., J. Med. Chem., 37 (1994) 1385.
2. Ajay, Walters, W.P. and Murcko, M.A., J. Med. Chem., 41 (1998) 3314.
3. Sadowski, J. and Kubinyi, H., J. Med. Chem., 41 (1998) 3325.
4. Tarbit, M.H. and Berman, J., Curr. Opin. Chem. Biol., 2 (1998) 411 and references cited therein.
5. Clark, D.E. and Pickett, S.D., Drug Discov. Today, 5 (2000) 49 and references cited therein.
6. Goldstein, G.W. and Betz, A.L., Sci. Am., 255 (1986) 74.
7. Greig, N.H., Brossi, A., Pei, X.F., Ingram, D.K., and Soncrant, T.T. (Eds.), In New Concepts of a Blood-Brain Barrier; Greenwood, J., et al., Plenum, New York, NY, 1995, pp. 251-264.
8. deVries, H.E., Kuiper, J., De Boer, A.G., van Berkel, T.J.C. and Breimer, D.D., Pharmacol. Rev., 49 (1997) 143.
9. Partridge, W.M., J. Neurochem., 70 (1998) 1781.
10. Pardridge, W.M., Drug Discov. Today, 6 (2001) 1.
11. Tamai, I. and Tsuji, A., Adv. Drug. Deliv. Rev., 19 (1996) 401.
12. Eddy, E.P., Maleef, B.E., Hart, T.K. and Smith, P.L., Adv. Drug Deliv. Rev., 23 (1997) 185.
13. Reichel, A. and Begley, D.J., Pharm. Res., 15 (1998) 1270.
14. Cecchelli, R., Dehouck, B., Descamps, L., Fenart, L., Buee-Scherrer, V., Duhem, C., Landquist, S., Rentfel, M., Torpier, G. and Dehouck, M.P., Adv. Drug Deliv. Rev., 36 (1999) 165.
15. Hansch, C., Björkroth, J.P. and Leo, A., J. Pharm. Sci., 76 (1987) 663.
16. Gupta, S.P., Chem. Rev., 89 (1989) 1765.
17. Basak, S.C., Gutte, B.D. and Drewes, L.R., Pharm. Res., 13 (1996) 775.
18. Kansy, M. and van de Waterbeemd, H., Chimia, 46 (1992) 299.
19. Young, R.C., Mitchell, R.C., Brown, T.H., Ganellin, C.R., Griffiths, R., Jones, M., Rana, K.K., Saunders, D., Smith, I.R., Sore, N.E. and Wilks, T.J., J. Med. Chem., 31 (1988) 656.
20. Levin, V.A., J. Med. Chem., 23 (1980) 682.
21. Chadha, H., Abraham, M.H. and Mitchell, R.C., Proceedings of an International Conference on the New Concept of a Blood-Brain Barrier, London, 1994.
22. Seelig, A., Gottschlich, R., and Dervent, R.M., Proc. Natl. Acad. Sci. USA, 91 (1994) 68.
23. Abraham, M.H., Chadha, H.S. and Mitchell, R.C., J. Pharm. Sci., 83 (1994) 1257.
24. Abraham, M.H., Chadha, H.S. and Mitchell, R.C., Drug Des. Discov., 13 (1995) 123.
25. Keserü, G.M. and Molnár, L., J. Chem. Inf. Comput. Sci., 41 (2001) 210.
26. Lombardo, F., Blake, J.F. and Curatolo, J.W., J. Med. Chem., 39 (1996) 4750.
27. Norinder, U., Sjöberg, P. and Österberg, T., J. Pharm. Sci., 87 (1998) 952.
28. Wold, S., Johansson, E. and Cocchi, M. (Eds.), PLS - Partial Least Squares Projection to Latent Structures. In: 3D QSAR in Drug Design; Kubinyi, H. (Ed.) ESCOM, Leiden, The Netherlands, 1993, pp. 523-550.
29. Wold, S. (Ed.), In Chemometric Methods in Molecular Design; van de Waterbeemd, H., VCH, Weinheim, Germany, 1995, pp. 195-218.
30. Crivori, P., Cruciani, G., Carrupt, P. and Testa, B., J. Med. Chem., 43 (2000) 2204.
31. Luco, J.M., J. Chem. Inf. Comput. Sci., 39 (1999) 396.
32. Rose, K., Hall, L.H. and Kier, L.B., J. Chem. Inf. Comput. Sci., 42 (2002) 651.
33. Lobell, M., Molnár, L. and Keserü, G.M., J. Pharm. Sci., 92 (2003) 360.
34. Liu, R., Sun, H. and So, S.S., J. Chem. Ind. Comput. Sci., 41 (2001) 1623.
35. Clark, D.E., J. Pharm. Sci., 88 (1999) 815.
36. Clark, D.E., J. Pharm. Sci., 88 (1999) 807.
37. ClogP. Daylight Chemical Information Software, version 4.51. Daylight Chemical Information Inc., Mission Viejo, CA.
38. Moriguchi, I., Hirono, S., Liu, Q., Nakagome, I. and Matsushita, Y., Chem. Pharm. Bull., 40 (1992) 127.
39. van de Waterbeemd, H., Camenisch, G., Folkers, G., Chretien, J. and Raevsky, O., J. Drug Target, 6 (1998) 151.
40. Fischer, H., Gottschlich, R. and Seelig, A., J. Membr. Biol., 165 (1998) 201.
41. Ajay, Bemis, G.W. and Murcko, M.A., J. Med. Chem., 42 (1999) 4942.
42. Comprehensive Medicinal Chemistry Release 94.1 is available from MDL Information Systems Inc., San Leandro, CA.
43. MACCS-II Drug Data Report is available from MDL Information Systems Inc., San Leandro, CA.
44. Hansch, C., Leo, A. and Hoekman, D., Exploring QSAR, Vol. 1. Fundamentals and Applications in Chemistry and Biology; Vol. 2. Hydrophobic, Electronic, and Steric Constants; American Chemical Society, Washington, DC, 1995.
45. Structure-Property Correlations in Drug Research; van de Waterbeemd, H., VCH, Weinheim, Germany, 1995, Vol. 3.
46. Rogers, D. and Hopfinger, A.J., J. Chem. Inf. Comput. Sci., 34 (1994) 854.
47. Rogers, D. (Ed.), In Genetic Algorithms in Molecular Modeling; Devillers, J., Academic, London, 1996.
48. Prous Science Synthline® Drug Synthesis Database on CD-ROM, Barcelona, Philadelphia, Feb. 2000 release.
49. Structures that resulted in inappropriate conformations (cisamide bond or skewed conformation for the cyclohexyl ring) were identified and re-optimized.
50. Rappe, A.K., Casewit, C.J., Colwell, K.S., Goddard, W.A. and Skiff, W.M., J. Am. Chem. Soc., 114 (1992) 10024.
51. 2 with the van der Waals radii reported in references 20 and 21. In this case, the van der Waals surface area is calculated and therefore the water probe radius is set to 0.0.
52. Wessel, M.D., Jurs, P.C., Tolan, J.W. and Muskal, S.M., J. Chem. Inf. Comput. Sci., 38 (1998) 726.
53. Jacobs, M.H. Diffusion Processes; Springer-Verlag, Berlin, Germany, 1935, p. 13.
54. Viswanadhan, V.N., Ghose, A.K., Revankar, G.R. and Robins, R.K., J. Chem. Inf. Comput. Sci., 29 (1989) 163 and references cited therein.
55. It is important to note that these models merely predict the permeation across the BB and is by no means a measure of the compounds potency at the CNS or other ligand binding sites. Many other determinants affect whether a drug would be a CNS agent, including metabolism in the CNS, efflux processes or failure to bind to receptor in the CNS, none of which would be described in logBB models. Further, some agents may permeate the CNS but have little noticeable effect and therefore their activities are not labeled in such a way as to be termed CNS active. A discussion of these caveats is found in the work of reference 15.
56. Stanton, D.T. and Jurs, P.C., Anal. Chem., 62 (1990) 2323.
57. Hall, L.H., Kier, L.B. and Brown, B.B., J. Chem. Inf. Comput. Sci., 35 (1995) 1074.
58. Lloyd, E.J. and Andrews, P.R., J. Med. Chem., 29 (1986) 453.
59. Kaliszan, R. and Markuszewski, M., Int. J. Pharm., 145 (1966) 9.
60. Chikhale, E.G., Ng, K., Burton, P.S. and Borchardt, R.T., Pharm. Res., 3 (1994) 412.
61. Lipinski, C.A., Lombardo, F., Dominy, B.W and Feeney, P.J., Adv. Drug Deliv. Rev., 23 (1997) 3.
62. 2 users manual for the types of atoms considered as hydrogen bond donor and acceptor. In version 4.0, a hydroxyl is both a hydrogen bond acceptor (HBA) and a hydrogen bond donor (HBD). A carbonyl oxygen is only an HBA; an amide N is a HBD and not an HBA. An N atom with less than 3 bonds is an HBA, a tetrahedral N with 3 bonds and sum of bond orders equal to 3 is an HBA and all N atoms with less than 3 bonds is an HBA.
63. Compounds Amiodarone, Coumarin, Diltiazem, Doxylamine, Ebastine, Loratadine, Neostigmine, and Pheniramine do not have any H-bond donor atoms.