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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Patent
1,2,4-TRIAZOLO[4,3-a]PYRIDINE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF MGLUR2 RECEPTORS
José Maria Cid-Núñez,Andrés Avelino Trabanco-Suárez,Juan Antonio Vega Ramiro,Daniel Oehlrich,Gary Tresadern,Gregor James Macdonald +5 more
TL;DR: In this article, a triazolo[4,3-a]pyridine derivatives of Formula (I) were described, where all radicals are defined as defined in the claims.
Journal ArticleDOI
Mineralocorticoid receptor antagonists: identification of heterocyclic amide replacements in the oxazolidinedione series.
Jason M. Cox,Hong D. Chu,Christine Yang,Hong C. Shen,Zhicai Wu,Jaume Balsells,Alejandro Crespo,Patricia Brown,Beata Zamlynny,Judyann Wiltsie,Joseph Clemas,Jack Gibson,Lisa Contino,JeanMarie Lisnock,Gaochao Zhou,Margarita Garcia-Calvo,Thomas Bateman,Ling Xu,Xinchun Tong,Martin Crook,Peter J. Sinclair +20 more
TL;DR: Structural-activity relationship efforts focused on improving lipophilic ligand efficiency (LLE) while maintaining nuclear hormone receptor selectivity and reasonable pharmacokinetic profiles.
Journal ArticleDOI
Toward lead-oriented synthesis: one-pot version of Castagnoli condensation with nonactivated alicyclic anhydrides.
Sergey V. Ryabukhin,Dmitriy M. Panov,Dmitriy M. Panov,Dmitry S. Granat,Dmitry S. Granat,Eugeniy N. Ostapchuk,Dmitriy V. Kryvoruchko,Oleksandr O. Grygorenko +7 more
TL;DR: One-pot variation of Castagnoli condensation, that is, reaction of cyclic anhydrides, amines, and aldehydes, has been developed as a combinatorial approach to 1,2-disubstituted 5-oxopyrrolidine- and 6-Oxopiperidine-3-carboxylic acids, as well as their benzo-analogues.
Journal ArticleDOI
Advancing the activity cliff concept, part II.
TL;DR: Up-to-date results of systematic analyses of the ligand efficiency and lipophilic efficiency relationships between activity cliff-forming compounds, which further increase their attractiveness for the practice of medicinal chemistry.
Journal ArticleDOI
Synergistic catalysis on Fe–N x sites and Fe nanoparticles for efficient synthesis of quinolines and quinazolinones via oxidative coupling of amines and aldehydes
TL;DR: Correction for ‘Synergistic catalysis on Fe–Nx sites and Fe nanoparticles for efficient synthesis of quinolines and quinazolinones via oxidative coupling of amines and aldehydes’.
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.