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
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Medicinal chemistry in drug discovery in big pharma: past, present and future.
TL;DR: The changes in synthetic and medicinal chemistry and related drug discovery science as practiced in big pharma over the past few decades are described, predominantly driven by wider changes in society namely the computer, internet and globalisation.
Journal ArticleDOI
Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton’s Tyrosine Kinase
Smith Christopher,Douglas R. Dougan,Mallareddy Komandla,Toufike Kanouni,Beverly M. Knight,J. David Lawson,Mark Sabat,Ewan Taylor,Phong H. Vu,Corey Wyrick +9 more
TL;DR: The discovery and optimization of a series of 4-aminocinnoline-3-carboxamide inhibitors of Bruton's tyrosine kinase are reported, resulting in the identification of a lead compound which reduced paw swelling in a dose- and exposure-dependent fashion in a rat model of collagen-induced arthritis.
Journal ArticleDOI
Recent advances in physicochemical and ADMET profiling in drug discovery.
Jianling Wang,Suzanne Skolnik +1 more
TL;DR: Recent advances in accurate assessment of solubility and other physicochemical parameters are reviewed and the impact of these tools on assisting drug‐discovery teams in establishing in vitro–in vivo correlation (IVIVC) as well as structure–property relationship (SPR) will be presented.
Journal ArticleDOI
Identification of C-2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2.
Mark Zak,Christopher A. Hurley,Stuart Ward,Philippe Bergeron,Kathy Barrett,Mercedesz Balazs,Wade S. Blair,Richard James Bull,Paroma Chakravarty,Christine Chang,Peter H. Crackett,Gauri Deshmukh,Jason DeVoss,Peter S. Dragovich,Charles Eigenbrot,Charles Ellwood,Simon Gaines,Nico Ghilardi,Paul Gibbons,Stefan Gradl,Peter Gribling,Chris Hamman,Eric Harstad,Peter Hewitt,Adam R. Johnson,Tony Johnson,Jane R. Kenny,Michael F. T. Koehler,Pawan Bir Kohli,Sharada Labadie,Wyne P. Lee,Jiangpeng Liao,Marya Liimatta,Rohan Mendonca,Raman Narukulla,Rebecca Pulk,Austin John Reeve,Scott Savage,Steven Shia,Micah Steffek,Savita Ubhayakar,Anne van Abbema,Ignacio Aliagas,Barbara Avitabile-Woo,Yisong Xiao,Jing Yang,Janusz J. Kulagowski +46 more
TL;DR: Analysis of historical data from related molecules was used to develop a set of physicochemical compound design parameters to impart desirable properties such as acceptable membrane permeability, potent whole blood activity, and a high degree of metabolic stability which culminated in the identification of a highly JAK1 selective compound exhibiting favorable oral bioavailability.
Journal ArticleDOI
In Vivo Phenotypic Screening for Treating Chronic Neuropathic Pain: Modification of C2-Arylethynyl Group of Conformationally Constrained A3 Adenosine Receptor Agonists
Dilip K. Tosh,Amanda Finley,Silvia Paoletta,Steven M. Moss,Zhan-Guo Gao,Elizabeth T. Gizewski,John A. Auchampach,Daniela Salvemini,Kenneth A. Jacobson +8 more
TL;DR: The structural range of orally active A3AR agonists for chronic pain treatment has been expanded, with more efficacious analogues (in vivo) contained the following C2-arylethynyl groups.
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.