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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Structure-activity study leading to identification of a highly active thienopyrimidine based EGFR inhibitor.
Steffen Bugge,Svein Jacob Kaspersen,Synne Larsen,Unni Nonstad,Geir Bjørkøy,Geir Bjørkøy,Eirik Sundby,Bård Helge Hoff +7 more
TL;DR: Based on the thieno[2,3-d]pyrimidine scaffold, a series of new 4-amino-6-aryl thienopyrimidines have been prepared and evaluated as EGFR tyrosine kinase inhibitors finding three structures with EGFR IC50 < 1 nM.
Journal ArticleDOI
Screening for Small Molecules' Bilayer-Modifying Potential Using a Gramicidin-Based Fluorescence Assay
TL;DR: The assay is based on measuring the time course of fluorescence quenching in fluorophore-loaded large unilamellar vesicles, due to entry of a gramicidin channel-permeable quencher, and is scalable and suitable for both mechanistic studies and high-throughput screening for bilayer-perturbing, potential off-target effects.
Journal ArticleDOI
Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2) ligands.
Tatsuki Koike,Takafumi Takai,Yasutaka Hoashi,Masaharu Nakayama,Yohei Kosugi,Masato Nakashima,Shin-ichi Yoshikubo,Keisuke Hirai,Osamu Uchikawa +8 more
TL;DR: Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2) agonist 4d with good oral absorption and blood-brain barrier (BBB) penetration in rats.
Journal ArticleDOI
Privileged scaffolds in lead generation.
Hongyu Zhao,Justin Dietrich +1 more
TL;DR: The principle of privileged scaffolds has greatly enhanced and empowered current lead generation technologies and its role in the design of ligands targeting protein-protein interactions, multiple ligands and warhead-based ligands is reviewed.
Journal ArticleDOI
Increasing small molecule drug developability in sub-optimal chemical space
Timothy John Ritchie,Simon J. F. Macdonald,Simon Peace,Stephen D. Pickett,Christopher N. Luscombe +4 more
TL;DR: In this paper, OPLS regression models were constructed to determine which physico-chemical properties were most correlated with developability, and the results suggested that whilst certain molecule properties were important for developability across all chemical space, such as heteroaliphatic ring count, positive ionisable group count and H-bond donor character exhibited varying degrees of importance depending on the clog P/Mw region.
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.