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
Rapid discovery of a novel series of Abl kinase inhibitors by application of an integrated microfluidic synthesis and screening platform.
Bimbisar Desai,Karen Dixon,Elizabeth Farrant,Qixing Feng,Karl Richard Gibson,Willem P. van Hoorn,James Edward John Mills,Trevor Morgan,David M. Parry,Manoj K. Ramjee,Christopher N. Selway,Gary J. Tarver,Gavin A. Whitlock,Adrian G. Wright +13 more
TL;DR: A flow technology platform integrating the key elements of structure-activity relationship (SAR) generation to the discovery of novel Abl kinase inhibitors is reported, which has the potential to greatly reduce the time and cost of drug discovery within the hit-to-lead and lead optimization phases.
Journal ArticleDOI
Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models.
Richard J. Weaver,Eric A.G. Blomme,Amy E. Chadwick,Ian M. Copple,Helga H.J. Gerets,Christopher E. Goldring,André Guillouzo,Philip G. Hewitt,Magnus Ingelman-Sundberg,Klaus Gjervig Jensen,Satu Juhila,Ursula Klingmüller,Gilles Labbe,Michael J. Liguori,Cerys A. Lovatt,Paul Morgan,Dean J. Naisbitt,Raymond Pieters,Jan Snoeys,Bob van de Water,Dominic P. Williams,B. Kevin Park +21 more
TL;DR: Current understanding of the mechanisms mediating DILI is discussed and a vision of a roadmap for the development of predictive preclinical models of human DILi is proposed through an academic–industry collaboration.
Journal ArticleDOI
Fragment-based drug discovery.
TL;DR: Two concepts underlie the appeal of fragment-based drug discovery (FBDD): first, chemical space can be more efficiently probed by screening collections of small fragments rather than libraries of larger molecules, and second, the binding efficiency per atom is at least as high as for larger hit molecules.
Journal ArticleDOI
Opportunities for therapeutic antibodies directed at G-protein-coupled receptors
TL;DR: The progress made by targeting GPCRs with antibody-based therapeutics, as well as technical hurdles to overcome, are presented and discussed in this Review.
Journal ArticleDOI
Amino acids as the nitrogen-containing motifs in copper-catalyzed domino synthesis of N-heterocycles.
TL;DR: A copper-catalyzed domino method for synthesis of quinazolinones has been developed using readily available α-amino acids as the nitrogen-containing motifs and should provide a new and useful strategy for construction of N-heterocycles.
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.