Lead- and drug-like compounds: the rule-of-five revolution

• Published in: Drug discovery today. Technologies 2004-12, Vol.1 (4), p.337-341
• Main Author: Lipinski, Christopher A.
• Format: Article
• Language: English
• ISSN: 1740-6749; 1740-6749
• DOI: 10.1016/j.ddtec.2004.11.007

Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochemical features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clinical success. Physicochemical features of CNS drugs and features related to CNS blood–brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compounds differ from those of drug-like compounds is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chemical tools to probe biology space. All these topics frame the scope of this short review/perspective. Han van de Waterbeemd, Christopher Kohl – Pfizer Global Research & Development, Sandwich Laboratories, PDM (Pharmacokinetics, Dynamics and Metabolism), Sandwich, Kent, UK CT13 9NJ In the past, many clinical candidates failed during development. The reasons for failure are now much better understood. The author of this contribution, Chris Lipinski, was among the first to point out that drugs typically have physicochemical and structural properties within certain ranges. This review discusses the original rule-of-five concept and its variants, to be used in the design of orally active compounds. He also compares the concepts of drug-like, lead-like, and CNS-like compounds and drugs. It is important to consider differences better oral and non-oral drugs. Finally, the new idea of tool-like compounds is presented.