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
Novel acidic 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).
James S. Scott,Joanne deSchoolmeester,Elaine Kilgour,Rachel M. Mayers,Martin J. Packer,David J. Hargreaves,Stefan Gerhardt,Derek Ogg,Amanda Rees,Nidhal Selmi,Andrew Stocker,John G. Swales,Paul Robert Owen Whittamore +12 more
TL;DR: The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.
Journal ArticleDOI
MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation
TL;DR: An integrated, multiobjective optimization workflow (MOARF) for directed medicinal chemistry design that couples a rule-based molecular fragmentation scheme with a pharmacophore fingerprint-based fragment replacement algorithm to broaden the scope of reconnection options considered in the generation of potential solution structures is described.
Journal ArticleDOI
Heart Regeneration: Opportunities and Challenges for Drug Discovery with Novel Chemical and Therapeutic Methods or Agents
TL;DR: The recent advances in these areas are outlined and both the modality and progress are described, including novel screening strategies to identify hits, and the upcoming challenges and opportunities to develop these hits into pharmaceuticals, at which chemistry plays a key role.
Journal ArticleDOI
Secondary pharmacology: screening and interpretation of off-target activities - focus on translation.
Steven Whitebread,Berengere Dumotier,Duncan Armstrong,Alexander Fekete,Shanni Chen,Andreas Hartmann,Patrick Y. Muller,Laszlo Urban +7 more
TL;DR: The progress of secondary pharmacology during the past decade is reviewed and its applications and impact in drug discovery are highlighted and demonstrated.
Journal ArticleDOI
Synthesis and structure-activity relationships of indazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.
Panayiotis A. Procopiou,John Barrett,Nick Barton,Malcolm Begg,David E. Clapham,Royston C. B. Copley,Alison J. Ford,Rebecca H. Graves,David A. Hall,Ashley Paul Hancock,Alan P. Hill,Heather Hobbs,Simon Teanby Hodgson,Coline Jumeaux,Yannick M. L. Lacroix,Afjal Hussain Miah,Karen M. L. Morriss,Deborah Needham,Emma B. Sheriff,Robert J. Slack,Claire E. Smith,Steven L. Sollis,Hugo Staton +22 more
TL;DR: A series of indazole arylsulfonamides synthesized and examined as human CCR4 antagonists suggested the presence of an important intramolecular interaction in the active conformation.
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.