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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Impact of Physicochemical Properties on Dose and Hepatotoxicity of Oral Drugs
TL;DR: A database containing maximum daily doses of 1841 marketed oral drugs was used to examine the influence of physicochemical properties on dose and hepatotoxicity, and a simple decision tree model predicted "No DilI" versus "Most DILI" outcomes with 82% accuracy.
THEMED SECTION: QT SAFETY REVIEW Value of non-clinical cardiac repolarization assays in supporting the discovery and development of safer medicines
TL;DR: The integrated risk assessment was reviewed, the benefit–risk for compound progression was re‐assessed, and the impact of non‐clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval was illustrated.
Journal ArticleDOI
A Screening Assay Cascade to Identify and Characterize Novel Selective Estrogen Receptor Downregulators (SERDs).
Rowena Callis,Alfred A. Rabow,Michael Tonge,Robert Hugh Bradbury,Mairi Challinor,Karen Roberts,Karen Jones,Graeme Walker +7 more
TL;DR: An endogenous cell-imaging strategy is used that has both the throughput and sensitivity to support a large-scale hit-to-lead program to identify novel SERD compounds with improved properties such as oral bioavailability and the potential of increased efficacy compared to currently marketed drug treatments.
Journal ArticleDOI
Increasing the delivery of next generation therapeutics from high throughput screening libraries
TL;DR: This work examines how best to identify medium to low molecular weight compounds from large diversity screening sets and increase downstream success in the pharmaceutical industry.
Journal ArticleDOI
Value of non-clinical cardiac repolarization assays in supporting the discovery and development of safer medicines.
TL;DR: The impact of non-clinical QT-related data to support compound progression throughout the drug discovery and development phases, and regulatory approval of a compound was discussed in this paper, where the authors provided a review of the impact of such data on compound progression.
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.