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
Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy.
Beatriz Baragaña,Neil R. Norcross,Caroline Wilson,Achim Porzelle,Irene Hallyburton,Raffaella Grimaldi,Maria Osuna-Cabello,Suzanne Norval,Jennifer Riley,Laste Stojanovski,Frederick R. C. Simeons,Paul G. Wyatt,Michael J. Delves,Stephan Meister,Sandra Duffy,Vicky M. Avery,Elizabeth A. Winzeler,Robert E. Sinden,Sergio Wittlin,Sergio Wittlin,Julie A. Frearson,David W. Gray,Alan H. Fairlamb,David Waterson,Simon F. Campbell,Paul Willis,Kevin D. Read,Ian H. Gilbert +27 more
TL;DR: The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described and a novel mechanism of action, inhibition of translation elongation factor 2 (PfEF2), led to progression of 2 to preclinical development.
Journal ArticleDOI
Innovative polymeric system (IPS) for solvent-free lipophilic drug transdermal delivery via dissolving microneedles
Manita Dangol,Huisuk Yang,Cheng Guo Li,Shayan Fakhraei Lahiji,Suyong Kim,Yonghao Ma,Hyungil Jung +6 more
TL;DR: It is shown that IPS based DMN with powder capsaicin enhances the therapeutic effect for treatment of the rheumatic arthritis in a DBA/1 mouse model compared to a solvent-based system, indicating the promising potential of this new solvent-free platform for lipophilic drug delivery.
Journal ArticleDOI
Thermodynamic optimisation in drug discovery: a case study using carbonic anhydrase inhibitors.
Andrew D. Scott,Christopher Phillips,Alexander Alex,Maria M Flocco,Andrew F. Bent,Amy Randall,Ronan O'Brien,Luminita Damian,Lyn H. Jones +8 more
TL;DR: It is demonstrated that with recent advances in ITC technology and comparing subtly modified ligands against the same target, under identical conditions, and with X-ray data support, thermodynamic measurements can provide medicinal chemists with another differentiator in their quest to discover the best lead compounds.
Journal ArticleDOI
Targeting G-quadruplex nucleic acids with heterocyclic alkaloids and their derivatives
TL;DR: In this review, the authors provide a brief, up-to-date summary of heterocyclic alkaloids and their derivatives targeting G-quadruplexes.
Journal ArticleDOI
Making medicinal chemistry more effective—application of Lean Sigma to improve processes, speed and quality
Shalini Andersson,Alan Armstrong,Annika Björe,Sue Bowker,Steve Chapman,Robert D. M. Davies,Craig S. Donald,Bryan J. Egner,Thomas Elebring,Sara Holmqvist,Tord Inghardt,Petra Johannesson,Magnus Johansson,Craig Johnstone,Paul D. Kemmitt,Jan Kihlberg,Pernilla Korsgren,Malin Lemurell,Jane E. Moore,Jonas A. Pettersson,Helen Pointon,Fritiof Ponten,Paul Schofield,Nidhal Selmi,Paul Robert Owen Whittamore +24 more
TL;DR: Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made, and the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically.
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.