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
Promiscuity and selectivity of bitter molecules and their receptors.
Antonella Di Pizio,Masha Y. Niv +1 more
TL;DR: Selectivity/promiscuity profile of bitter taste receptors and their compounds was explored by a chemoinformatic approach, and TAS2R-promiscuous and TAs2Rs-selective bitter molecules were found to differ in chemical features, which allowed the prediction of bitter ligand selectivity toward TAS1Rs.
Journal ArticleDOI
Discovery of novel benzylidene-1,3-thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases.
Les A. Dakin,Michael Howard Block,Huawei Chen,Erin Code,James E. Dowling,Xiaomei Feng,Andrew D. Ferguson,Isabelle Green,Alexander Hird,Tina Howard,Erika Krasnickas Keeton,Michelle Lamb,Paul Lyne,Hannah Pollard,Jon Read,Allan Wu,Tao Zhang,Xiaolan Zheng +17 more
TL;DR: Novel substituted benzylidene-1,3-thiazolidine-2,4-diones (TZDs) have been identified as potent and highly selective inhibitors of the PIM kinases.
Journal ArticleDOI
Compound Aggregation in Drug Discovery: Implementing a Practical NMR Assay for Medicinal Chemists
Steven R. LaPlante,Rebekah J. Carson,James Gillard,Norman Aubry,René Coulombe,Sylvain Bordeleau,Pierre R. Bonneau,Michael J. Little,Jeff A. O'Meara,Pierre L. Beaulieu +9 more
TL;DR: This work introduces the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that can be performed on equipment prevalent in most synthetic chemistry departments and shows that (1)H NMR resonances are sensitive to large molecular-size entities and to smaller multimers and mixtures of species.
Journal ArticleDOI
Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design.
TL;DR: In this paper, the design and applications of bioisosteric replacements for a phenyl ring that have provided practical solutions to a range of developability problems frequently encountered in lead optimization campaigns are discussed.
Journal ArticleDOI
Visible-Light-Mediated Aerobic Oxidation of N-Alkylpyridinium Salts under Organic Photocatalysis
TL;DR: A highly efficient and environmentally friendly visible light-mediated aerobic oxidation of readily available N-alkylpyridinium salts has been developed with Eosin Y as the organic photocatalyst and air as the terminal oxidant, and the reaction provided quinolones and isoquinolones in good yields.
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.