Relating molecular properties and in vitro assay results to in vivo drug disposition and toxicity outcomes

Journal of Medicinal Chemistry

Volumn 55, Issue 14, 2012, Pages 6455-6466

  Sutherland, Jeffrey J ^a   Raymond, John W ^a   Stevens, James L ^a   Baker, Thomas K ^a   Watson, David E ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

PROTEIN DERIVATIVE;

ANIMAL EXPERIMENT; ARTICLE; CELL KILLING; CONTROLLED STUDY; DATA BASE; DRUG ABSORPTION; DRUG CYTOTOXICITY; DRUG DESIGN; DRUG DISPOSITION; DRUG DISTRIBUTION; DRUG EXCRETION; DRUG METABOLISM; DRUG SOLUBILITY; DRUG STRUCTURE; FEMALE; HUMAN; IN VITRO STUDY; IN VIVO STUDY; LIVER CELL; MALE; NONHUMAN; PREDICTION; RAT; SINGLE DRUG DOSE;

ABSORPTION; ANIMALS; BIOLOGICAL AVAILABILITY; DRUG DISCOVERY; FEMALE; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS; RATS; SOLUBILITY; THERMODYNAMICS;

EID: 84864268973     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300684u     Document Type: Article

References (28)

1. Paul, S. M.; Mytelka, D. S.; Dunwiddie, C. T.; Persinger, C. C.; Munos, B. H.; Lindborg, S. R.; Schacht, A. L. How to improve R&D productivity: the pharmaceutical industry's grand challenge Nature Rev. Drug. Discovery 2010, 9, 203-214
2. Kerns, D.; Di, L. Drug-like Properties: Concepts, Structure Design and Methods: from ADME to Toxicity Optimization. Academic Press: Burlington, MA, 2008; p 552.
3. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug. Delivery Rev. 1997, 23, 3-25
4. 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.; Zhang, Y. Physiochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872-4875
5. Veber, D. F.; Johnson, S. R.; Cheng, H. Y.; Smith, B. R.; Ward, K. W.; Kopple, K. D. Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 2002, 45, 2615-2623
6. Waring, M. J. Defining optimum lipophilicity and molecular weight ranges for drug candidates-Molecular weight dependent lower logD limits based on permeability Bioorg. Med. Chem. Lett. 2009, 19, 2844-2851
7. Vieth, M.; Siegel, M. G.; Higgs, R. E.; Watson, I. A.; Robertson, D. H.; Savin, K. A.; Durst, G. L.; Hipskind, P. A. Characteristic Physical Properties and Structural Fragments of Marketed Oral Drugs J. Med. Chem. 2004, 47, 224-232
8. Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb J. Med. Chem. 2008, 51, 817-834
9. Johnson, T. W.; Dress, K. R.; Edwards, M. Using the Golden Triangle to optimize clearance and oral absorption Bioorg. Med. Chem. Lett. 2009, 19, 5560-5564
10. Wenlock, M. C.; Austin, R. P.; Barton, P.; Davis, A. M.; Leeson, P. D. A comparison of physiochemical property profiles of development and marketed oral drugs J. Med. Chem. 2003, 46, 1250-1256
11. Leeson, P. D.; Davis, A. M. Time-related differences in the physical property profiles of oral drugs J. Med. Chem. 2004, 47, 6338-6348
12. Kenny, P. W.; Sadowski, J. Structure modification in chemical databases. In Chemoinformatics in Drug Discovery; Oprea, T., Ed.; Wiley-VCH: Weinheim, 2004; pp 271-285.
13. Leach, A. G.; Jones, H. D.; Cosgrove, D. A.; Kenny, P. W.; Ruston, L.; MacFaul, P.; Wood, J. M.; Colclough, N.; Law, B. Matched molecular pairs as a guide in the optimization of pharmaceutical properties: a study of aqueous solubility, plasma protein binding and oral exposure J. Med. Chem. 2006, 49, 6672-6682
14. Barro, R.; Lee, J.-W. A New Data Set of Educational Attainment in the World, 1950-2010. NBER Working Paper 15902; National Bureau of Economic Research: Cambridge, MA, 2010.
15. 2 of 0.5 in forward validation on 67 compounds. The machine learning method used is described in: Erickson, J. A.; Mader, M. M.; Watson, I. A.; Webster, Y. W.; Higgs, R. E.; Bell, M. A.; Vieth, M. Structure-guided expansion of kinase fragment libraries driven by support vector machine models. Biochim. Biophys. Acta, Proteins Proteomics 2010, 1804, 642-652.
16. Ito, K.; Houston, J. B. Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes Pharm. Res. 2004, 21, 785-792
17. Mohutsky, M. A.; Chien, J. Y.; Ring, B. J.; Wrighton, S. A. Predictions of the in vivo clearance of drugs from rate of loss using human liver microsomes for phase I and phase II biotransformations Pharm. Res. 2006, 23, 654-662
18. Stevens, J. L.; Baker, T. K. The future of drug safety testing: expanding the view and narrowing the focus Drug Discovery Today 2009, 14, 162-167
19. Tsao, S. C.; Iga, T.; Sugiyama, Y.; Hanano, M. Effect of chlorpromazine on isolated rat hepatocytes Biochem. Pharmacol. 1982, 31, 491-497
20. Klaunig, J. E.; Baker, T. K. Morphological evaluation of gap junctional intracellular communication. In Methods in Toxicology: In Vitro Toxicity Indicators; Tyson, C. A.; Frazier, J. M., Eds.; Academic Press: San Diego, 1994; Vol. 2, pp 72-80.
21. Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties J. Med. Chem. 2000, 43, 3714-3717
22. Smith, D. A.; Di, L.; Kerns, E. H. The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery Nature Rev. Drug. Discovery 2010, 9, 929-939
23. Raymond, J. W.; Watson, I. A.; Mahoui, A. Rationalizing lead optimization by associating quantitative relevance with molecular structure modification J. Chem. Inf. Model. 2009, 49, 1952-1962
24. Vieth, M.; Sutherland, J. J. Dependence of molecular properties on proteomic family for marketed oral drugs J. Med. Chem. 2006, 49, 3451-3453
25. Congreve, M.; Carr, R.; Murray, C.; Jhoti, H. A "rule of three" for fragment-based lead discovery? Drug Discovery Today 2003, 8, 876-877
26. Oprea, T. I.; Davis, A. M.; Teague, S. J.; Leeson, P. D. Is there a difference between leads and drugs? A historical perspective J. Chem. Inf. Comput. Sci. 2001, 41, 1308-1315
27. Cramer, J. W.; Mattioni, B. E.; Savin, K. A. Strategies for conducting ADME studies during lead generation in the drug discovery process IDrugs 2010, 13, 857-861
28. Crissman, J. W.; Goodman, D. G.; Hildebrandt, P. K.; Maronpot, R. R.; Prater, D. A.; Riley, J. H.; Seaman, W. J.; Thake, D. C. Best practices guideline: toxicologic histopathology Toxicol. Pathol. 2004, 32, 126-131