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
Discovery of Phenylpropanoic Acid Derivatives Containing Polar Functionalities as Potent and Orally Bioavailable G Protein-Coupled Receptor 40 Agonists for the Treatment of Type 2 Diabetes
Satoshi Mikami,Shuji Kitamura,Nobuyuki Negoro,Shinobu Sasaki,Masami Suzuki,Yoshiyuki Tsujihata,Takeshi Miyazaki,Ryo Ito,Nobuhiro Suzuki,Junichi Miyazaki,Takashi Santou,Naoyuki Kanzaki,Miyuki Funami,Toshimasa Tanaka,Tsuneo Yasuma,Yu Momose +15 more
TL;DR: Several 4'-alkoxybiphenyl derivatives showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties, and exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.
Journal ArticleDOI
Matched molecular pair analysis: significance and the impact of experimental uncertainty.
TL;DR: The connection between overall MMPA statistics and individual pairs is illustrated with a detailed comparison of average CHEMBL hERG MMPA results versus pairs with extreme transformation effects, and it is found that significant transformation effects agree very well if the experimental uncertainty is considered.
Book ChapterDOI
Combining NMR and X-ray Crystallography in Fragment-Based Drug Discovery: Discovery of Highly Potent and Selective BACE-1 Inhibitors
Daniel F. Wyss,Yu-Sen Wang,Hugh L. Eaton,Corey Strickland,Johannes H. Voigt,Zhaoning Zhu,Andrew Stamford +6 more
TL;DR: In this article, a successful fragment-based drug discovery (FBDD) campaign is described that has allowed the development of a clinical candidate for BACE-1, a challenging CNS drug target.
Journal ArticleDOI
6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors
Patrick James Sarver,Michael G. Acker,Jeffrey T. Bagdanoff,Zhouliang Chen,Ying-Nan Chen,Ho Man Chan,Brant Firestone,Michelle Fodor,Jorge Garcia Fortanet,Huaixiang Hao,Murphy Hentemann,Mitsunori Kato,Robert Koenig,Laura R. LaBonte,Gang Liu,Shumei Liu,Chen Liu,Eric McNeill,Morvarid Mohseni,Martin Sendzik,Travis Stams,Stan Spence,Victoriano Tamez,Ritesh Bhanudasji Tichkule,Christopher Towler,Hongyun Wang,Ping Wang,Sarah Williams,Bing Yu,Matthew J. LaMarche +29 more
TL;DR: This work improves upon the previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via theAllosteric mechanism.
Journal ArticleDOI
Catechol pyrazolinones as trypanocidals: fragment-based design, synthesis, and pharmacological evaluation of nanomolar inhibitors of trypanosomal phosphodiesterase B1.
Kristina M. Orrling,Chimed Jansen,Xuan Lan Vu,Vreni Balmer,Patrick Bregy,Anitha Shanmugham,Paul England,David S. Bailey,Paul Cos,Louis Maes,Emily R. Adams,Erika van den Bogaart,Eric Chatelain,Jean-Robert Ioset,Andrea C. van de Stolpe,Stèphanie Zorg,Johan Veerman,Thomas Seebeck,Geert Jan Sterk,Iwan J. P. de Esch,Rob Leurs +20 more
TL;DR: The mode of action of 20b was investigated with recombinantly engineered trypanosomes expressing a cAMP-sensitive FRET sensor, confirming a dose-response related increase of intracellular cAMP levels in trypanOSomes, and further validate the TbrPDEB family as antitrypanosomal target.
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.