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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ADMET rules of thumb II: A comparison of the effects of common substituents on a range of ADMET parameters.
TL;DR: A systematic analysis of data generated in key in vitro assays within GSK has been undertaken to identify what impact a range of common substituents have on arange of ADMET parameters.
Journal ArticleDOI
Visible-Light-Mediated Efficient Metal-Free Catalyst for α-Oxygenation of Tertiary Amines to Amides
TL;DR: A metal-free system has been discovered for the efficient α-oxygenation of tertiary amines to the corresponding amides using oxygen as an oxidant using visible-light-mediated oxygenation reaction.
Journal ArticleDOI
Ligand-receptor interaction platforms and their applications for drug discovery.
TL;DR: The key biochemical aspects of drug–target interactions are reviewed, and the detection principles of various ligand-binding techniques in the context of their primary applications for drug discovery and development are discussed.
Journal ArticleDOI
Pyrazole NNRTIs 4: selection of UK-453,061 (lersivirine) as a development candidate.
Charles E. Mowbray,Catherine Burt,Romuald Corbau,Simon Gayton,Michael Hawes,Manos Perros,Isabelle Tran,David Price,Faye J. Quinton,Matthew D. Selby,Stupple Paul Anthony,Rob Webster,Anthony Wood +12 more
TL;DR: The analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development are described.
Journal ArticleDOI
Investigating the Influence of (Deoxy)fluorination on the Lipophilicity of Non‐UV‐Active Fluorinated Alkanols and Carbohydrates by a New log P Determination Method
Bruno Linclau,Zhong Wang,Guillaume Compain,Vincent Paumelle,Clement Q. Fontenelle,Neil J. Wells,Alexander C. Weymouth-Wilson +6 more
TL;DR: A new variation of the shake‐flask log P determination method is presented, enabling the measurement of log’P for fluorinated compounds with or without UV activity regardless of whether they are hydrophilic or lipophilic.
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.