Overview on the Rule of Five

Michael P. Pollastri1

1 Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts
Publication Name:  Current Protocols in Pharmacology
Unit Number:  Unit 9.12
DOI:  10.1002/0471141755.ph0912s49
Online Posting Date:  June, 2010
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Abstract

In the mid‐ to late 1990s, because of the drug discovery paradigm shift from phenotypic screens to combinatorial chemistry and high‐throughput screening, the physicochemical properties of exploratory drug molecules displayed a dramatic shift toward higher molecular weight and lipophilicity. In response, Lipinski and coworkers reported an analysis of compounds that successfully navigated Phase I and entered into Phase II clinical studies, and correlated the computed physicochemical properties of these molecules to their aqueous solubility, permeability, and oral bioavailability. In doing so, the authors created the “Rule of Five,” a mnemonic tool for medicinal chemists to use to quickly assess compounds during the drug discovery and optimization process with respect to the compounds' likelihood to display good solubility and permeability profiles. This overview outlines the basis for the Rule of Five, the ways in which it has been applied, and its impact on drug discovery and development. Curr. Protoc. Pharmacol. 49:9.12.1‐9.12.8. © 2010 by John Wiley & Sons, Inc.

Keywords: Rule of Five; computational alert; drug absorption; drug permeation; molecular weight; lipophilicity; H‐bond donors and acceptors; aqueous solubility

     
 
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Table of Contents

  • Introduction
  • Trends in Drug Discovery Leading to the Rule of Five
  • Methodology
  • Formulation of “The Rule of Five (Ro5)”
  • Exceptions, Variations, and Limitations to the Ro5
  • Implementation of the Ro5
  • Impact of the Ro5 on Molecular Weight and Lipophilicity Trends
  • Variations of the Ro5
  • Discussion and Summary
  • Acknowledgement
  • Literature Cited
  • Tables
     
 
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Materials

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Literature Cited

Literature Cited
   Abraham, M.H. 1993. Hydrogen bonding. 31. Construction of a scale of solute effective or summation hydrogen‐bond basicity. J. Phys. Org. Chem. 6:660‐684.
   Abraham, M.H., Keseru, G.M., and Makara, G.M. 2009. The influence of lead discovery strategies on the properties of drug candidates. Nat. Rev. Drug Disc. 8:203‐212.
   Ajay, Bemis, G.W., and Murcko, M. 1999. Designing libraries with CNS activity. J. Med. Chem. 42:4842‐4951.
   Baillie, A. and Whittaker, M. 2007. Pre‐formulation: The key to successful transition into pre‐clinical development. Sp. Chem. Mag. 27:30‐33
   Blake, J.F. 2003. Examination of the computed molecular properties of compounds selected for clinical development. BioTechniques 34:S16‐S20.
   Broach, J.R. and Thorner, J. 1996. High‐throughput screening for drug discovery. Nature 384:14‐16.
   Chou, J.T. and Jurs, P.C. 1979. Computer‐assisted computation of partition coefficients from molecular structures using fragment constants. J. Chem. Inf. Comp. Sci. 19:172‐178.
   Cohen, B.E. and Bangham, A.D. 1972. Diffusion of small non‐electrolytes across liposome membranes. Nature 236:173‐174.
   Congreve, M., Carr, R., Murray, C., and Jhoti, H. 2003. A ‘rule of three’ for fragment‐based lead discovery? Drug Disc.Today 8:876‐877.
   Friesen, D.T., Shanker, R., Crew, M., Smithey, D.T., Curatolo, W.J., and Nightingale, J.A.S. 2008. Hydroxypropyl methylcellulose acetate succinate‐based spray‐dried dispersions: An overview. Mol. Pharmaceut. 5:1003‐1019.
   Ghose, A.K. and Crippen, G.M. 1986. Atomic physicochemical parameters for three‐dimensional structure‐directed quantitative structure‐activity relationships I. Partition coefficients as a measure of hydrophobicity. J. Comput. Chem. 7:565‐577.
   Hillgren, K.M., Kato, A., and Borchardt, R.T. 1995. In vitro systems for studying intestinal drug absorption. Med. Res. Rev. 15:83‐109.
   Keseru, G.M. and Makara, G.M. 2009. The influence of lead discovery strategies on the properties of drug candidates. Nat. Rev. Drug Discov. 8:203‐212.
   Kola, I. and Landis, J. 2004. Opinion: Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Disc. 3:711‐716.
   Leeson, P.D. and Springthorpe, B. 2007. The influence of drug‐like concepts on decision making in medicinal chemistry. Nat. Rev. Drug Disc. 6:881‐890.
   Lipinski, C.A. 2000a. Drug‐like properties and the causes of poor solubility and poor permeability. J. Pharmacol. Toxicol. Meth. 44:235‐249.
   Lipinski, C.A. 2000b. Changes in the Profiles of Drug Properties: An Experimental, Computational and Informatics Perspective. American Chemical Society National Meeting, March 26‐30, 2000, San Francisco, Calif. Available online: http://www.pharmalabauto.com/Solubility/Presentations/ppt/Lipinski/Lipinski9/ppframe.htm.
   Lipinski, C.A. 2002. Physicochemical properties and the discovery of orally active drugs: Technical and people issues. In Molecular Informatics: Confronting Complexity (M.G. Hicks and C. Kettner, eds.) pp. 1‐20. Proc. Beilstein‐Institute Workshop, May 13‐16, 2002, Bozen, Italy.
   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 Deliv. Rev. 23:3‐25.
   Loftsson, T., Jarho, P., Masson, M., and Jaervinen, T. 2005. Cyclodextrins in drug delivery. Expert Opin. Drug. Deliv. 2:335‐3351.
   Moriguchi, I., Hirono, S., Liu, Q., Nakagome, Y., and Matsushita, Y. 1992. Simple method of calculating octanol/water partition coefficient. Chem. Pharm. Bull. 42:976‐978.
   Navia, M.A. and Chaturvedi, P.R. 1996. Design principles for orally bioavailable drugs. Drug Dev. Today 1:179‐189.
   Overington, J.P., Al‐Lazikani, B., and Hopkins, A.L. 2006. How many drug targets are there? Nat. Rev. Drug. Disc. 5:993‐999.
   Pardridge, W.M. 1995. Transport of small molecules through the blood‐brain barrier: Biology and methodology. Adv. Drug Deliv. Rev. 15:5‐36.
   Paterson, D.A., Conradi, R.A., Hilgers, A.R., Vidmar, T.J., and Burton, P.S. 1994. A non‐aqueous partitioning system for predicting the oral absorption potential of peptides. Quant. Struct.‐Act. Relat. 13:4‐10.
   Proudfoot, J.R. 2002. Drugs, leads, and drug‐likeness: An analysis of some recently launched drugs. Bioorg. Med. Chem. Lett. 12:1647‐1650.
   Raevsky, O.A., Grigorev, V.Y., Kireev, D.B., and Zefirov, N.S. 1992. Complete thermodynamic description of H‐bonding in the framework of multiplicative approach. Quant. Struct.‐Act. Relat. 11:49‐63.
   Raevsky. O.A., Schaper, K‐J., and Seydel, J.K. 1995. H‐bond contribution to octanol‐water partition coefficients of polar compounds. Quant. Struct‐Act. Relat. 14:433‐436.
   Testa, B., Carrupt, P.‐A., Gaillard, P., Billois, F., and Weber, P. 1996. Lipophilicity in molecular modeling. Pharm. Res. 13:335‐343.
   United States Food and Drug Administration. 2004. Innovation or stagnation: Challenges and opportunity on the critical path to new medical products; http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html.
   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.
   Veith, M. and Sutherland, J.J. 2006. Dependence of molecular properties on proteomic family for marketed oral drugs. J. Med. Chem. 49:3451‐3453.
   Zhang, M.‐Q. and Wilkinson, B. 2007. Drug discovery beyond the ‘rule of five’. Curr. Opin. Biotech. 18:478‐488.
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