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
Scaffold-Hopping Approach To Discover Potent, Selective, and Efficacious Inhibitors of NF-κB Inducing Kinase
Nicole Blaquiere,Georgette Castanedo,Jason Burch,Leonid M. Berezhkovskiy,Hans Brightbill,Suzanne Brown,Connie Chan,Po-Chang Chiang,James J. Crawford,Teresa Dong,Peter W. Fan,Jianwen Feng,Nico Ghilardi,Robert Godemann,Emily B. Gogol,Alice Grabbe,Alison J Hole,Baihua Hu,Sarah G. Hymowitz,Moulay Hicham Alaoui Ismaili,Hoa Le,Patrick Lee,Wyne P. Lee,Xingyu Lin,Ning Liu,Paul A. McEwan,Brent S. McKenzie,Hernani L Silvestre,Eric Suto,Swathi Sujatha-Bhaskar,Guosheng Wu,Lawren C. Wu,Yamin Zhang,Zoe Zhong,Steven T. Staben +34 more
TL;DR: Lead chemical series of NIK inhibitors identified through a scaffold-hopping strategy exhibited selective inhibition of LTβR-dependent p52 translocation and transcription of NF-κB2 related genes and are shown to have a favorable pharmacokinetic profile across species.
Patent
1, 4-disubstituted 3-cyano-pyridone derivatives and their use as positive allosteric modulators of MGLUR2-receptors
Hassan Julien Imogai,José Maria Cid-Núñez,Jose Ignacio Andres-Gil,Andrés Avelino Trabanco-Suárez,Julen Oyarzabal Santamarina,Frank Matthias Dautzenberg,Gregor James Macdonald,Shriley Elizabeth Pullan,Robert Johannes Lütjens,Guillaume Albert Jacques Duvey,Vanthea Nhem,Terry Patrick Finn,Gagik Melikyan +12 more
TL;DR: Pyridinone as mentioned in this paper is a positive allosteric modulator of metabotropic receptors -sub-type 2 ("mGluR2") which is useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction.
Journal ArticleDOI
Efficiency of hit generation and structural characterization in fragment-based ligand discovery.
TL;DR: Emerging understanding of the efficiency and operative aspects of hit generation and structural characterization in FBLD suggests that this method should be well suited for academic ligand development of chemical tools and experimental therapeutics.
Journal ArticleDOI
Fragment-to-Lead Medicinal Chemistry Publications in 2019.
Wolfgang Jahnke,Daniel A. Erlanson,Iwan J. P. de Esch,Christopher N. Johnson,Paul N. Mortenson,Yuji Ochi,Tatsuya Urushima +6 more
TL;DR: This Perspective summarizes successful fragment-to-lead stories published in 2019 and the analysis of screening methods, optimization strategies, and molecular properties of hits and leads are presented in the hope of informing best practices for FBDD.
Journal ArticleDOI
The CSD Drug Subset: The Changing Chemistry and Crystallography of Small Molecule Pharmaceuticals.
Mathew J. Bryant,Simon N. Black,Helen Blade,Robert Docherty,Andrew G. P. Maloney,Stefan C. Taylor +5 more
TL;DR: The generation and statistical analysis of the CSD drug subset is reported: a subset of the Cambridge Structural Database consisting of every published small-molecule crystal structure containing an approved drug molecule.
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.