Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery

ACS Chemical Neuroscience

Volumn 7, Issue 6, 2016, Pages 767-775

  Wager, Travis T ^a   Hou, Xinjun ^a   Verhoest, Patrick R ^a   Villalobos, Anabella ^a  

^a PFIZER INC   (United States)

Author keywords

Attrition; central nervous system (CNS); CNS candidates; CNS drug design; CNS drugs; CNS MPO; desirability score; efficacious drug concentration (Ceff); Harrington optimization; human liver microsome stability; hydrogen bond donor; lipophilicity; Madin Darby canine kidney; molecular weight; most basic pKa; multiparameter optimization (MPO); multivariant optimization; P glycoprotein (P gp); passive permeability; polarity; topological polar surface area; unbound intrinsic clearance

Indexed keywords

CYCLOBENZAPRINE; DEXTROPROPOXYPHENE; EMONAPRIDE; NORTRIPTYLINE; TERGURIDE; TRAZODONE; MULTIDRUG RESISTANCE PROTEIN;

ALGORITHM; APPARENT PERMEABILITY; ARTICLE; BLOOD BRAIN BARRIER; CENTRAL NERVOUS SYSTEM MULTIPARAMETER OPTIMIZATION; DRUG DEVELOPMENT; DRUG PENETRATION; FALL RISK ASSESSMENT; HUMAN; HUMAN CELL; INTRINSIC CLEARANCE; INVESTIGATIVE PROCEDURES; METABOLIC STABILITY; PHYSICAL CHEMISTRY; PKA; PRIORITY JOURNAL; ANIMAL; CENTRAL NERVOUS SYSTEM; DRUG DESIGN; DRUG EFFECTS; METABOLISM; PERMEABILITY; TRANSPORT AT THE CELLULAR LEVEL;

ALGORITHMS; ANIMALS; BIOLOGICAL TRANSPORT; BLOOD-BRAIN BARRIER; CENTRAL NERVOUS SYSTEM; DRUG DESIGN; HUMANS; P-GLYCOPROTEIN; PERMEABILITY;

EID: 84974832037     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/acschemneuro.6b00029     Document Type: Article

References (16)

1. Wager, T. T., Chandrasekaran, R. Y., Hou, X., Troutman, M. D., Verhoest, P. R., Villalobos, A., and Will, Y. (2010) Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes ACS Chem. Neurosci. 1, 420-434 10.1021/cn100007x
2. Harrington, E. C., Jr. (1965) The desirability function Indust. Qual. Control 21, 494-498
3. Wager, T. T., Hou, X., Verhoest, P. R., and Villalobos, A. (2010) Moving beyond rules: The development of a central nervous system multiparameter optimization (CNS MPO) approach to enable alignment of druglike properties ACS Chem. Neurosci. 1, 435-449 10.1021/cn100008c
4. Gunaydin, H. (2015) Probabilistic Approach to Generating MPOs and Its Application as a Scoring Function for CNS Drugs ACS Med. Chem. Lett. 7, 89-93 10.1021/acsmedchemlett.5b00390
5. Bickerton, G. R., Paolini, G. V., Besnard, J., Muresan, S., and Hopkins, A. L. (2012) Quantifying the chemical beauty of drugs Nat. Chem. 4, 90-98 10.1038/nchem.1243
6. 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 10.1016/j.bmcl.2008.07.071
7. Ghose, A. K., Herbertz, T., Hudkins, R. L., Dorsey, B. D., and Mallamo, J. P. (2012) Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery ACS Chem. Neurosci. 3, 50-68 10.1021/cn200100h
8. Wager, T. T., Kormos, B. L., Brady, J. T., Will, Y., Aleo, M. D., Stedman, D. B., Kuhn, M., and Chandrasekaran, R. Y. (2013) Improving the odds of success in drug discovery: Choosing the best compounds for in vivo toxicology studies J. Med. Chem. 56, 9771-9779 10.1021/jm401485p
9. Ertl, P. (2008) Polar surface area Methods Princ. Med. Chem. 37, 111-126 10.1002/9783527621286.ch5
10. Rankovic, Z. (2015) CNS Drug Design: Balancing Physicochemical Properties for Optimal Brain Exposure J. Med. Chem. 58, 2584-2608 10.1021/jm501535r
11. (2014) SAS JMP, version 10, SAS Institute, Inc., Cary, NC.
12. (2015) TIBCO Spotfire, version 6.5.3, TIBCO Software Inc., Somerville, MA.
13. Di, L., Whitney-Pickett, C., Umland, J. P., Zhang, H., Zhang, X., Gebhard, D. F., Lai, Y., Federico, J. J., 3rd, Davidson, R. E., Smith, R., Reyner, E. L., Lee, C., Feng, B., Rotter, C., Varma, M. V., Kempshall, S., Fenner, K., El-Kattan, A. F., Liston, T. E., and Troutman, M. D. (2011) Development of a New Permeability Assay Using Low-Efflux MDCKII Cells J. Pharm. Sci. 100, 4974-4985 10.1002/jps.22674
14. Feng, B., Mills, J. B., Davidson, R. E., Mireles, R. J., Janiszewski, J. S., Troutman, M. D., and de Morais, S. 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 10.1124/dmd.107.017434
15. 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 10.1177/0091270009333209
16. 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 10.1124/dmd.107.020131