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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Dynamic structure based pharmacophore modeling of the Acetylcholinesterase reveals several potential inhibitors.
TL;DR: Multi-conformation dynamic pharmacophore models from the donepezyl-binding pocket based on highly populated structures chosen from molecular dynamics simulations were used for screening compounds that can properly bind acetylcholinesterase.
Journal ArticleDOI
Copper-Catalyzed Chan-Lam Cyclopropylation of Phenols and Azaheterocycles.
Joseph Derosa,Miriam L. O’Duill,Matthew Holcomb,Mark N. Boulous,Ryan L. Patman,Fen Wang,Michelle Tran-Dubé,Indrawan James Mcalpine,Keary M. Engle +8 more
TL;DR: This method is operationally convenient to perform and provides a simple, strategic disconnection toward the synthesis of cyclopropyl aryl ethers and cycloprostyl amine derivatives bearing an array of functional groups.
Journal ArticleDOI
A framework for grouping nanoparticles based on their measurable characteristics
TL;DR: An experimental methodology coupled with mathematical and statistical modeling that can serve as a prototype for a rigorous framework that aids in the ability to group nanomaterials together and to facilitate the subsequent analysis of trends in data based on quantitative modeling of nanoparticle-specific structure–activity relationships is proposed.
Journal ArticleDOI
Phenotypic screening and fragment-based approaches to the discovery of small-molecule bromodomain ligands
TL;DR: The progress that has been made to date in the discovery of small-molecule bromodomain ligands is described, with particular emphasis on the roles played by phenotypic screening and fragment-based approaches.
Journal ArticleDOI
Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept.
Kate Ashton,Kristin L. Andrews,Marion C. Bryan,Jie Chen,Kui Chen,Michelle Chen,Samer Chmait,Michael Croghan,Rod Cupples,Christopher H. Fotsch,Joan Helmering,Steve R. Jordan,Robert J.M. Kurzeja,Klaus Michelsen,Lewis D. Pennington,Steve F. Poon,Glenn Sivits,Gwyneth Van,Steve L. Vonderfecht,Robert C. Wahl,Jiandong Zhang,David Lloyd,Clarence Hale,David J. St. Jean +23 more
TL;DR: The identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket is reported, and the potency of the initial hit was improved to provide 25 (AMG-1694).
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.