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
More filters
Journal ArticleDOI
Fluorine in medicinal chemistry.
TL;DR: This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.
Journal ArticleDOI
Network pharmacology: the next paradigm in drug discovery.
TL;DR: A new appreciation of the role of polypharmacology has significant implications for tackling the two major sources of attrition in drug development--efficacy and toxicity.
Journal ArticleDOI
The Medicinal Chemist's Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates
TL;DR: The reaction types used in the pursuit of novel drug candidates are analyzed to evaluate their frequency of occurrence, alongside other factors such as drug likeness, chirality, and the number of steps to each derivative.
Journal ArticleDOI
Rings in Drugs
TL;DR: Analysis of rings, ring systems, and frameworks in drugs listed in the FDA Orange Book gives insight into the chemical novelty of drugs and potentially efficient ways to assess compound libraries and develop compounds from hit identification to lead optimization and beyond.
Journal ArticleDOI
The ChEMBL bioactivity database: an update
A. Patrícia Bento,Anna Gaulton,Anne Hersey,Louisa J. Bellis,Jon Chambers,Mark Davies,Felix A. Kruger,Yvonne Light,Lora Mak,Shaun McGlinchey,Michal Nowotka,George Papadatos,Rita Santos,John P. Overington +13 more
TL;DR: More comprehensive tracking of compounds from research stages through clinical development to market is provided through the inclusion of data from United States Adopted Name applications and a new richer data model for representing drug targets has been developed.
References
More filters
Journal Article
Degradative transport of cationic amphiphilic drugs across phospholipid bilayers. Discussion
M. Baciu,Sarra C. Sebai,Oscar Ces,Xavier Mulet,James A. Clarke,Gemma C. Shearman,Robert V. Law,Richard H. Templer,Christophe Plisson,Christine A. Parker,Antony D. Gee,E. T. Samulski,A. A. Kornyshev,H. F. Gleeson,N. W. Roberts +14 more
TL;DR: Evidence is presented that one of the largest classes of pharmaceutical drug molecules, the cationic amphiphilic drugs (CADs), does so via a catalytic reaction that degrades the phospholipid fabric of the membrane, and it is probable that this process is a significant mechanism for drug transport.
Journal Article
Principles and practice of Hansch analysis: a guide to structure-activity correlation for the medicinal chemist.
Journal ArticleDOI
Identification and evaluation of molecular properties related to preclinical optimization and clinical fate.
TL;DR: This perspective will cover recent efforts that have had the greatest influence on defining the optimal range of physical properties of compounds that are intended to act as human therapeutic agents and examine the optimal physicochemical properties for oral absorption based on solubility, permeability, and a few easily computed parameters.
Book ChapterDOI
Predicting oral absorption and bioavailability.
TL;DR: Very promising progress has been made using a combination of several in vitro measures, as well as the development of in silico tools in predicting oral absorption and bioavailability.
Journal Article
Lipophilicity and biological acitivity. Drug transport and drug distribution in model systems and in biological systems.
TL;DR: Combination of the pH-partition theory with the bilinear model leads to a simple quantitative model for the precise description of the relationships between lipophilicity, degree of ionization, and absorption, distribution and biological activity of drugs.