Journal ArticleDOI
The influence of drug-like concepts on decision-making in medicinal chemistry
TLDR
Analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development.Abstract:
The application of guidelines linked to the concept of drug-likeness, such as the 'rule of five', has gained wide acceptance as an approach to reduce attrition in drug discovery and development. However, despite this acceptance, analysis of recent trends reveals that the physical properties of molecules that are currently being synthesized in leading drug discovery companies differ significantly from those of recently discovered oral drugs and compounds in clinical development. The consequences of the marked increase in lipophilicity--the most important drug-like physical property--include a greater likelihood of lack of selectivity and attrition in drug development. Tackling the threat of compound-related toxicological attrition needs to move to the mainstream of medicinal chemistry decision-making.read more
Citations
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Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters
TL;DR: In this manuscript, several composite parameters, or efficiency indices, are examined utilizing theoretical and experimental matched molecular pair analyses in order to understand the basis for how each will perform under varying scenarios of molecular optimizations.
Journal ArticleDOI
Acidic and basic drugs in medicinal chemistry: a perspective.
TL;DR: This review summarizes the potential advantages and disadvantages of both acidic and basic drugs and provides some new analyses based on recently available public data.
Journal ArticleDOI
Limitations and lessons in the use of X-ray structural information in drug design.
TL;DR: Some of the uncertainties introduced during the process of deriving an atomic model from the experimentally observed electron density are highlighted with recent examples from the literature, together with snippets of advice for the medicinal chemist embarking on using X-ray crystal structure information in a drug discovery programme.
Journal ArticleDOI
Review and analysis of FDA approved drugs using lipid-based formulations
TL;DR: A review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems is provided and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule.
Journal ArticleDOI
Molecular inflation, attrition and the rule of five
TL;DR: Overall, there is demonstrable physical property attrition in moving from patents to candidate drugs to marketed drugs, and attrition can therefore be improved by ensuring candidate drug quality is 'fit for purpose.
References
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Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Journal ArticleDOI
Molecular properties that influence the oral bioavailability of drug candidates.
Daniel F. Veber,Stephen R. Johnson,Hung-Yuan Cheng,Brian R. Smith,Keith W. Ward,Kenneth D. Kopple +5 more
TL;DR: Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count are found to be important predictors of good oral bioavailability, independent of molecular weight.
Journal ArticleDOI
Can the pharmaceutical industry reduce attrition rates
Ismail Kola,John Landis +1 more
TL;DR: The pharmaceutical industry faces considerable challenges, both politically and fiscally, and the fiscal pressures that face the industry from the perspective of R&D are dealt with.
Book
The Merck index
TL;DR: This CD-ROM provides the tools to draw structures and then search for them, and presents over 10,000 monographs which detail chemicals, drugs and biologicals, and describe a single substance or small group of related compounds.
Journal ArticleDOI
Lead- and drug-like compounds: the rule-of-five revolution.
TL;DR: This topic is explored in terms ofDrug-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.