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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Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field
TL;DR: All-atom molecular dynamics simulations were used to predict water-cyclohexane distribution coefficients of a range of small molecules as part of the SAMPL5 blind prediction challenge, and preliminary work suggests that the major source of error lies in the hydration free energy calculations.
Journal ArticleDOI
Janus Kinase Antagonists and Other Novel Small Molecules for the Treatment of Crohn's Disease.
TL;DR: There is an ongoing, unmet need for effective therapies for Crohn's disease, and multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1-phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies.
Journal ArticleDOI
Synthesis of pyridopyrazine-1,6-diones from 6-hydroxypicolinic acids via a one-pot coupling/cyclization reaction.
TL;DR: A facile one-pot synthesis of 3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-diones (pyridopyrazine) has been developed which employs a sequential coupling/cyclization reaction of 6-hydroxypicolinic acids and β-hydroxylamines.
Journal ArticleDOI
Development of N-methyl-(2-arylquinolin-4-yl)oxypropanamides as leads to PET radioligands for translocator protein (18 kDa).
TL;DR: In this article, the authors varied the known high-affinity TSPO ligand (l)-N,N-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)propanamide in its aryl scaffold, side chain tether, and pendant substituted amido group while retaining an N-methyl group as a site for labeling with carbon-11.
Journal ArticleDOI
What can we learn from the evolution of protein-ligand interactions to aid the design of new therapeutics?
Alicia P. Higueruelo,Adrian Schreyer,G. Richard J. Bickerton,Tom L. Blundell,William R. Pitt,William R. Pitt +5 more
TL;DR: It is shown that natural complexes typically engage in more polar contacts than synthetic molecules bound to proteins, and that the synthetic molecules also have a higher proportion of unmatched heteroatoms at the interface than the natural sets.
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.