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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Journal ArticleDOI
Scaffold distributions in bioactive molecules, clinical trials compounds, and drugs.
Ye Hu,Jürgen Bajorath +1 more
TL;DR: A comparative molecular scaffold analysis of three sets of compounds representing different stages in drug discovery: biologically active molecules (hits or leads), compounds in clinical trials, and registered/approved drugs.
Book ChapterDOI
Hit-to-Lead: Hit Validation and Assessment
TL;DR: A variety of approaches are described, including chemical assessment, the use of various computational approaches, a variety of counter-screens, and "orthogonal" biophysical assays using nuclear magnetic resonance, surface plasmon resonance, isothermal titration calorimetry or thermal shift assays as methods for validating and assessing the quality of hits.
Journal ArticleDOI
Enantiomeric pairs reveal that key medicinal chemistry parameters vary more than simple physical property based models can explain
Andrew G. Leach,Elizabeth Pilling,Alfred A. Rabow,Simone Tomasi,Nabil Asaad,Niklaas J. Buurma,Andrew Ballard,Stefania Narduolo +7 more
TL;DR: The analysis reveals that many properties are sensitive to changes in stereochemistry and quantifies this dependence and suggests an inherent advantage to lead optimization in a chiral series where improvement into an attractive part of chemical space might be complemented by a selection between two enantiomers with different pharmacokinetic or safety profiles.
Journal ArticleDOI
Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists
James O'Brien-Brown,Alexander Jackson,Tristan A. Reekie,Melissa L. Barron,Eryn L. Werry,Paolo Schiavini,Michelle McDonnell,Lenka Munoz,Shane M. Wilkinson,Benjamin Noll,Shudong Wang,Michael Kassiou +11 more
TL;DR: This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X7R antagonists, according to their inhibitory potency and antidepressant phenotype in behavioral studies.
Journal ArticleDOI
Design, synthesis and biological activity of phenoxyacetic acid derivatives as novel free fatty acid receptor 1 agonists.
TL;DR: Further chemical modification of this series of phenoxyacetic acid derivatives directed by ligand efficiency and ligand lipophilicity efficiency leads to the discovery of the promising candidate 16, an excellent FFA1 agonist with robust agonistic activity and desired LE and LLE values.
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.