Defining desirable central nervous system drug space through the alignment of molecular properties, in vitro ADME, and safety attributes

ACS Chemical Neuroscience

Volumn 1, Issue 6, 2010, Pages 420-434

  Wager, Travis T ^a,c   Chandrasekaran, Ramalakshmi Y ^a   Hou, Xinjun ^a   Troutman, Matthew D ^b   Verhoest, Patrick R ^a   Villalobos, Anabella ^a   Will, Yvonne ^c  

^a Neuroscience Medicinal Chemistry   (United States)

^b Dynamics and Metabolism Screening CoE ^*  (United States)

^c PFIZER INC   (United States)

Author keywords

Central nervous system (CNS); CNS candidates; CNS drugs; High throughput screening; Hydrogen bond donor; Lipophilicity; Madin Darby canine kidney; Molecular weight; Most basic pKa; Passive permeability; Polarity; Topological polar surface area

Indexed keywords

AMPHETAMINE; DOFETILIDE; GABAPENTIN; NICOTINE GUM; PRAMIPEXOLE; PREGABALIN;

ARTICLE; CELL VIABILITY; CENTRAL NERVOUS SYSTEM; DRUG ABSORPTION; DRUG BINDING; DRUG CLEARANCE; DRUG DISTRIBUTION; DRUG ELIMINATION; DRUG INHIBITION; DRUG METABOLISM; DRUG SAFETY; IN VITRO STUDY; LIPOPHILICITY; PHYSICOCHEMICAL MODEL; PRIORITY JOURNAL;

CELLULAR TOXICITY; CENTRAL NERVOUS SYSTEM (CNS); CNS CANDIDATES; CNS DRUGS; DOFETILIDE BINDING; DRUG-DRUG INTERACTIONS; HIGH-THROUGHPUT SCREENING; HUMAN LIVER MICROSOME STABILITY; HYDROGEN BOND DONOR; LIGAND EFFICIENCY; LIGAND-EFFICIENCY-DEPENDENT LIPOPHILICITY; LIGAND-LIPOPHILICITY EFFICIENCY; LIPOPHILICITY; MADIN-DARBY CANINE KIDNEY; MOLECULAR WEIGHT; MOST BASIC PKA; P-GLYCOPROTEIN; PASSIVE PERMEABILITY; POLARITY; TOPOLOGICAL POLAR SURFACE AREA; TRANSFORMED HUMAN LIVER EPITHELIAL CELLS; UNBOUND INTRINSIC CLEARANCE;

ANIMALS; CELL LINE; CELL SURVIVAL; CENTRAL NERVOUS SYSTEM; CENTRAL NERVOUS SYSTEM AGENTS; DOGS; DRUG DESIGN; EPITHELIAL CELLS; HUMANS; P-GLYCOPROTEIN; SAFETY; SOLUBILITY;

EID: 77953680038     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/cn100007x     Document Type: Article

References (35)

1. Kola, I. and Landis, J. (2004) Opinion: Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discovery 3, 711-716
2. O'Shea, R. and Moser, H. E. (2008) Physicochemical properties of antibacterial compounds: Implications for drug discovery J. Med. Chem. 51, 2871-2878
3. Leeson Paul, D. and Davis Andrew, M. (2004) Time-related differences in the physical property profiles of oral drugs J. Med. Chem. 47, 6338-6348
4. Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., and Kopple, K. D. (2002) Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 45, 2615-2623
5. Proudfoot, J. R. (2005) The evolution of synthetic oral drug properties Bioorg. Med. Chem. Lett. 15, 1087-1090
6. Leeson Paul, D. and Springthorpe, B. (2007) The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 6, 881-890
7. Gleeson, M. P. (2008) Generation of a set of simple, interpretable ADMET rules of thumb J. Med. Chem. 51, 817-834
8. Pajouhesh, H. and Lenz, G. R. (2005) Medicinal chemical properties of successful central nervous system drugs NeuroRX 2, 541-553
9. Lipinski, C. A. (2005) Filtering in drug discovery Annu. Rep. Comput. Chem. 1, 155-168
10. Hitchcock, S. A. and Pennington, L. D. (2006) Structure-brain exposure relationships J. Med. Chem. 49, 7559-7583
11. Leeson, P. D., Davis, A. M., and Steele, J. (2004) Drug-like properties: Guiding principles for design-or chemical prejudice? Drug Discovery Today: Technol. 1, 189-195
12. Abraham, M. H., Ibrahim, A., Zissimos, A. M., Zhao, Y. H., Comer, J., and Reynolds, D. P. (2002) Application of hydrogen bonding calculations in property based drug design Drug Discovery Today 7, 1056-1063
13. Lipinski, C. A., Lombardo, F., Dominy, B. W., and Feeney, P. J. (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 23, 3-25
14. Feng, B., Mills Jessica, B., Davidson Ralph, E., Mireles Rouchelle, J., Janiszewski John, S., Troutman Matthew, D., and de Morais Sonia, M. (2008) In vitro P-glycoprotein assays to predict the in vivo interactions of P-glycoprotein with drugs in the central nervous system Drug Metab. Dispos. 36, 268-275
15. Whalen, K., Gobey, J., and Janiszewski, J. (2006) A centralized approach to tandem mass spectrometry method development for high-throughput ADME screening Rapid Commun. Mass Spectrom. 20, 1497-1503
16. Abad-Zapatero, C. (2007) Ligand efficiency indices for effective drug discovery Expert Opin. Drug Discovery 2, 469-488
17. Keserue, G. M. and Makara, G. M. (2009) The influence of lead discovery strategies on the properties of drug candidates Nat. Rev. Drug Discovery 8, 203-212
18. Hughes, J. D., Blagg, J., Price, D. A., Bailey, S., DeCrescenzo, G. A., Devraj, R. V., Ellsworth, E., Fobian, Y. M., Gibbs, M. E., Gilles, R. W., Greene, N., Huang, E., Krieger-Burke, T., Loesel, J., Wager, T., Whiteley, L., and Zhang, Y. (2008) Physiochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 18, 4872-4875
19. Ertl, P., Rohde, B., and Selzer, P. (2000) Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its applications to the prediction of drug transport properties J. Med. Chem. 43, 3714-3717
20. Waring, M. J. (2009) Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower log D limits based on permeability Bioorg. Med. Chem. Lett. 19, 2844-2851
21. Ploemen, J.-P. H. T. M., Kelder, J., Hafmans, T., van de Sandt, H., van Burgsteden, J. A., Salemink, P. J. M., and van Esch, E. (2004) Use of physicochemical calculation of pKa and CLogP to predict phospholipidosis- inducing potential: A case study with structurally related piperazines Exp. Toxicol. Pathol. 55, 347-355
22. Gao, H., Yao, L., Mathieu, H. W., Zhang, Y., Maurer, T. S., Troutman, M. D., Scott, D. O., Ruggeri, R. B., and Lin, J. (2008) In silico modeling of nonspecific binding to human liver microsomes Drug Metab. Dispos. 36, 2130-2135
23. Hosea, N. A., Collard, W. T., Cole, S., Maurer, T. S., Fang, R. X., Jones, H., Kakar, S. M., Nakai, Y., Smith, B. J., Webster, R., and Beaumont, K. (2009) Prediction of human pharmacokinetics from preclinical information: Comparative accuracy of quantitative prediction approaches J. Clin. Pharmacol. 49, 513-533
24. Van de Waterbeemd, H., Smith, D. A., and Jones, B. C. (2001) Lipophilicity in PK design: Methyl, ethyl, futile J. Comput.-Aided Mol. Des.n 15, 273-286
25. Kaye, C. M., Haddock, R. E., Langley, P. F., Mellows, G., Tasker, T. C. G., Zussman, B. D., and Greb, W. H. (1989) A review of the metabolism and pharmacokinetics of paroxetine in man Acta Psychiatr. Scand., Suppl. 350, 60-75
26. Leach, A. R., Hann, M. M., Burrows, J. N., and Griffen, E. J. (2006) Fragment screening: An introduction Mol. BioSyst. 2, 429-446
27. Houck, K. A. and Kavlock, R. J. (2008) Understanding mechanisms of toxicity: Insights from drug discovery research Toxicol. Appl. Pharmacol. 227, 163-178
28. Miller, V. P., Stresser, D. M., Blanchard, A. P., Turner, S., and Crespi, C. L. (2000) Fluorometric high-throughput screening for inhibitors of cytochrome P450 Ann. N. Y. Acad. Sci. 919, 26-32
29. Fermini, B. and Fossa, A. A. (2003) The impact of drug-induced QT interval prolongation on drug discovery and development Nat. Rev. Drug Discovery 2, 439-447
30. Deacon, M., Singleton, D., Szalkai, N., Pasieczny, R., Peacock, C., Price, D., Boyd, J., Boyd, H., Steidl-Nichols, J. V., and Williams, C. (2007) Early evaluation of compound QT prolongation effects: A predictive 384-well fluorescence polarization binding assay for measuring hERG blockade J. Pharmacol. Toxicol. Methods 55, 238-247
31. Leeson, P. D. and Springthorpe, B. (2007) The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 6, 881-890
32. Walum, E., Hedander, J., and Garberg, P. (2005) Research perspectives for pre-screening alternatives to animal experimentation Toxicol. Appl. Pharmacol. 207, S393-S397
33. JMP. ((1989-2007) SAS JMP 7, SAS Institute, Inc. Cary, NC.
34. Spotfire. (1996-2007) Spotfire Decision Site 9, TIBCO Softrware Inc., Somerville, MA.
35. Hop, C. E. C. A., Cole, M. J., Davidson, R. E., Duignan, D. B., Federico, J., Janiszewski, J. S., Jenkins, K., Krueger, S., Lebowitz, R., Liston, T. E., Mitchell, W., Snyder, M., Steyn, S. J., Soglia, J. R., Taylor, C., Troutman, M. D., Umland, J., West, M., Whalen, K. M., Zelesky, V., and Zhao, S. X. (2008) High throughput ADME screening: Practical considerations, impact on the portfolio and enabler of in silico ADME models Curr. Drug Metab. 9, 847-853