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
The impact of aromatic ring count on compound developability: further insights by examining carbo- and hetero-aromatic and -aliphatic ring types.
TL;DR: Increasing aromatic ring count has a detrimental effect on human bioavailability parameters, and heteroaromatic ring count (but not other ring counts) has increased over time in marketed oral drugs.
Journal ArticleDOI
Fragment-Based Discovery of the Pyrazol-4-Yl Urea (at9283), a Multitargeted Kinase Inhibitor with Potent Aurora Kinase Activity.
Steven Howard,Valerio Berdini,John A. Boulstridge,Maria Grazia Carr,David M. Cross,Jayne Curry,Lindsay A. Devine,Theresa Rachel Early,Lynsey Fazal,Adrian Liam Gill,Michelle Heathcote,Sarita Maman,Julia E. Matthews,Rachel McMenamin,Eva Figueroa Navarro,Michael Alistair O'brien,Marc O'Reilly,David C. Rees,Matthias Reule,Dominic Tisi,Glyn Williams,Mladen Vinkovic,Paul Graham Wyatt +22 more
TL;DR: The identification of a clinical candidate via structure-based optimization of a ligand efficient pyrazole-benzimidazole fragment is described, which demonstrated in vivo efficacy in mouse xenograft models and is currently under evaluation in phase I clinical trials.
Journal ArticleDOI
Molecular obesity, potency and other addictions in drug discovery
TL;DR: The term Molecular Obesity is introduced to describe the authors' tendency to build potency into molecules by the inappropriate use of lipophilicity which leads to the premature demise of drug candidates.
Journal ArticleDOI
Constraining Cyclic Peptides To Mimic Protein Structure Motifs
TL;DR: This Review highlights examples of cyclic peptides that mimic three-dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic proteins and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.
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.