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
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Recent progress on nuclear receptor RORγ modulators.
TL;DR: This digest covers key developments around RORγ agonists, antagonists and inverse agonists; orthosteric and allosteric binders; and aims to summarize the available information concerning the potential utility of R ORγ modulators.
Journal ArticleDOI
Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain
Robert P. Law,Stephen John Atkinson,Paul Bamborough,Chun-wa Chung,Emmanuel Hubert Demont,Laurie J. Gordon,Matthew J Lindon,Rab K. Prinjha,Allan J. B. Watson,David Jonathan Hirst +9 more
TL;DR: Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2), culminating in potent BET inhibitors with BD2 selectivity.
Journal ArticleDOI
Ligand efficiency metrics in drug discovery: the pros and cons from a practical perspective
TL;DR: In this review, ligand efficiency metrics are described giving a balanced overview on their merits and points of weakness in order to enable the readers to gain an informed opinion.
Journal ArticleDOI
Exploring experimental and computational markers of cyclic peptides: Charting islands of permeability.
Conan K. Wang,Susan E. Northfield,Joakim E. Swedberg,Barbara Colless,Stephanie Chaousis,David Price,Spiros Liras,David J. Craik +7 more
TL;DR: A model describing the interplay between peptide permeability, lipophilicity and hydrogen bonding potential is proposed and supported by molecular dynamics simulations of the cyclic peptides calculated in explicit solvent, providing a structural basis for the observed correlations.
Journal ArticleDOI
Lipophilicity and biomimetic properties measured by HPLC to support drug discovery.
TL;DR: The published HPLC methods for lipophilicity, acid/base character, protein and phospholipid binding are critically reviewed and compared with each other using the solvation equation approach and the general relationships between the chemical structure and biomimetic HPLC properties are described.
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.