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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Combining label-free cell phenotypic profiling with computational approaches for novel drug discovery.
TL;DR: Combining label-free cell phenotypic profiling with computational approaches can provide a potential paradigm to accelerate novel drug discovery by taking advantages of the best of both approaches.
Journal ArticleDOI
Challenges with multi-objective QSAR in drug discovery.
TL;DR: QSAR models implemented in web platforms and workflows provide sequential SOO for multiple biological and toxicity end points, while MOO, still restricted to a limited number of objectives, is helpful for multi-target or selectivity design, as well as for model prioritization.
Journal ArticleDOI
Synthesis of tripeptides containing D-Trp substituted at the indole ring, assessment of opioid receptor binding and in vivo central antinociception.
TL;DR: The introduction of different substituents at the indole of D-Trp significantly influenced receptor affinities and resulted in serum stability and in a measurable effect on central antinociception in mice after ip administration.
Journal ArticleDOI
Chalcone derivatives targeting mitosis: synthesis, evaluation of antitumor activity and lipophilicity
Patricia Pinto,Carmen Mariana Machado,Joana Moreira,José Diogo P. Almeida,Patrícia M. A. Silva,Ana C. Henriques,José X. Soares,Jorge A. R. Salvador,Carlos A. M. Afonso,Madalena Pinto,Hassan Bousbaa,Honorina Cidade +11 more
TL;DR: Results indicate that compound 15 exerts its antiproliferative activity by affecting microtubules and causing cell death subsequently to a mitotic arrest, and thus has the potential for antitumor activity.
Journal ArticleDOI
Do Biologically Relevant Compounds Have More Chance To Be Drugs
TL;DR: The results suggest that compounds with higher BR have more chance to survive the drug development pipeline and the above conclusion is supported by the fact that compounds in the later development phases possess higher BR than those in the earlier phases.
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.