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
Exhaustive sampling of docking poses reveals binding hypotheses for propafenone type inhibitors of P-glycoprotein.
TL;DR: In this paper, five different propafenone derivatives with known structure-activity relationship (SAR) pattern were docked into homology models of the apo and the nucleotide-bound conformation of the transporter.
Journal ArticleDOI
Copper-catalyzed aerobic oxidative intramolecular alkene C-H amination leading to N-heterocycles.
TL;DR: A copper-catalyzed aerobic oxidative intramolecular alkene C-H amination has been developed using readily available substituted 3-benzylidene- 2-pyridin-2-ylmethyl-2,3-dihydro-isoindol-1-ones as the starting materials, and the corresponding N-heterocycles were obtained in good to excellent yields.
Journal ArticleDOI
Q)SAR Modeling and Safety Assessment in Regulatory Review
TL;DR: The ability to predict clinical safety based on chemical structures is becoming an increasingly important part of regulatory decision making with the standardization of analytical approaches, more complete and reliable data collection methods, and a better understanding of toxicity mechanisms.
Journal ArticleDOI
Cheminformatic tools for medicinal chemists.
TL;DR: This work states that, if underlying relation-ships between a given chemical structure and a host ofbiological end points exist and can be elucidated, drug dis-covery timelines can be significantly reduced, and prior knowledge of which mole-cules have the highest probability of success is worthy ofvigorous pursuit.
Book ChapterDOI
Reducing the Risk of Drug Attrition Associated with Physicochemical Properties
Paul D. Leeson,James Empfield +1 more
TL;DR: Adopting a “zero-tolerance” attitude to compound-based failure in the clinic would lead to fewer candidate nominations, but also to increased clinical success.
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.