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
Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency.
Christopher William Murray,Maria Grazia Carr,Owen Callaghan,Gianni Chessari,Miles Congreve,Suzanna Cowan,Joseph E. Coyle,Robert Downham,Eva Figueroa,Martyn Frederickson,Brent Graham,Rachel McMenamin,M. Alistair O’Brien,Sahil Patel,Theresa Rachael Phillips,Glyn Williams,Andrew James Woodhead,Alison Jo-Anne Woolford +17 more
TL;DR: The fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms and was optimized into a resorcinol lead that is now in clinical trials for the treatment of cancer.
Journal ArticleDOI
Discovery of PF-04457845: A Highly Potent, Orally Bioavailable, and Selective Urea FAAH Inhibitor
Douglas S. Johnson,Cory Michael Stiff,Lazerwith Scott E,Suzanne Ross Kesten,Lorraine Kathleen Fay,Mark Morris,David Beidler,Marya Liimatta,Sarah E. Smith,David T. Dudley,Nalini Sadagopan,Shobha N. Bhattachar,Stephen J. Kesten,Tyzoon K. Nomanbhoy,Benjamin F. Cravatt,Kay Ahn +15 more
TL;DR: Compound 23 has exquisite selectivity for FAAH relative to other members of the serine hydrolase superfamily as demonstrated by competitive activity-based protein profiling and is being evaluated in human clinical trials.
Journal ArticleDOI
Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development.
James J. Crawford,Adam R. Johnson,Dinah Misner,Lisa D. Belmont,Georgette Castanedo,Regina Choy,Melis Coraggio,Liming Dong,Charles Eigenbrot,Rebecca Erickson,Nico Ghilardi,Jonathan Hau,Arna Katewa,Pawan Bir Kohli,Wendy Lee,Joseph W. Lubach,Brent S. McKenzie,Daniel F. Ortwine,Leah Schutt,Suzanne Tay,Binqing Wei,Karin Reif,Lichuan Liu,Harvey Wong,Wendy B. Young +24 more
TL;DR: GDC-0853 has the potential to be a best-in-class Btk inhibitor for a wide range of immunological indications and demonstrates highly favorable safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles in preclinical and Phase 2 studies ongoing in patients with rheumatoid arthritis, lupus, and chronic spontaneous urticaria.
Journal ArticleDOI
New insights from structural biology into the druggability of G protein-coupled receptors
TL;DR: In this article, the authors review properties of GPCR binding sites, using a unique combination of calculated physicochemical properties and water energetics (GRID, WaterMap and SZMAP) to provide a new perspective and rational assessment of druggability for each gPCR target binding sites.
Journal ArticleDOI
Targeting ERK1/2 protein-serine/threonine kinases in human cancers.
TL;DR: Owing to the large variety of malignancies that are driven by dysregulation of the MAP kinase pathway, additional tumor types should be amenable to MAP kinases pathway inhibitor therapy and the addition of ERK inhibitors should prove helpful.
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.