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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Privileged Structures - Dream or Reality: Preferential Organization of Azanaphthalene Scaffold
TL;DR: It is shown that knowledge discovery in molecular databases can reveal interesting time-trends profiles for important classes of potentially privileged scaffolds in drugs and natural products, which are preferred by Nature in evolution.
Journal ArticleDOI
Mind and machine in drug design
TL;DR: After a difficult start, medicinal chemists are now ready to embrace AI-based methods and concepts in drug discovery, explains Gisbert Schneider.
Journal ArticleDOI
Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability
Martin Pettersson,Xinjun Hou,Max Kuhn,Travis T. Wager,Gregory W. Kauffman,Patrick Robert Verhoest +5 more
TL;DR: In this article, the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability was examined.
Journal ArticleDOI
Discovery of selective and noncovalent diaminopyrimidine-based inhibitors of epidermal growth factor receptor containing the T790M resistance mutation.
Emily J. Hanan,Charles Eigenbrot,Marian C. Bryan,Daniel J. Burdick,Bryan K. Chan,Yuan Chen,Jennafer Dotson,Robert Heald,Philip Stephen Jackson,Hank La,Michael D. Lainchbury,Shiva Malek,Hans E. Purkey,Gabriele Schaefer,Stephen P. Schmidt,Eileen Mary Seward,Steve Sideris,Christine Tam,Shumei Wang,Siew Kuen Yeap,Ivana Yen,Jianping Yin,Christine Yu,Inna Zilberleyb,Timothy P. Heffron +24 more
TL;DR: The evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors is described and two distinct binding modes revealed and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.
Journal ArticleDOI
Insights into molecular basis of cytochrome p450 inhibitory promiscuity of compounds.
Feixiong Cheng,Yue Yu,Yadi Zhou,Zhonghua Shen,Wen Xiao,Guixia Liu,Weihua Li,Philip W. Lee,Philip W. Lee,Yun Tang +9 more
TL;DR: An entropy-based index was defined to quantify the P450 inhibitory promiscuity of a compound based on a comprehensive data set, containing more than 11,500 drug-like compounds with inhibition against five major P450 isoforms, 1A2, 2C9,2C19, 2D6, and 3A4, and showed that there was a surprising level of P450 inhibition even for substrate specific P450.
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.