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
More filters
Journal ArticleDOI
Small and colorful stones make beautiful mosaics: fragment-based chemogenomics.
Chris de Graaf,Henry F. Vischer,Gerdien E. de Kloe,Albert J. Kooistra,Saskia Nijmeijer,Martien Kuijer,Mark H.P. Verheij,Paul England,Jacqueline E. van Muijlwijk-Koezen,Rob Leurs,Iwan J. P. de Esch,Iwan J. P. de Esch +11 more
TL;DR: The construction of a diverse fragment library and an analysis of the screening of six representative protein targets belonging to three diverse target classes using chemogenomics approaches are described, allowing the identification of unexpected similarities and differences in ligand binding properties and subtle ligand affinity and selectivity cliffs.
Journal ArticleDOI
Discovery of a Novel Series of N-Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase-2 Inhibitors
Kenjiro Sato,Hiroki Takahagi,Takeshi Yoshikawa,Shinji Morimoto,Takafumi Takai,Kousuke Hidaka,Masahiro Kamaura,Osamu Kubo,Ryutaro Adachi,Tsuyoshi Ishii,Toshiyuki Maki,Taisuke Mochida,Shiro Takekawa,Masanori Nakakariya,Nobuyuki Amano,Tomoyuki Kitazaki +15 more
TL;DR: Optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-N-[4-(trifloromethyl)phenyl]-2,3-dihydro-1H-indole-1
Journal ArticleDOI
Structure-Based Optimization of Small-Molecule Inhibitors for the β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction
TL;DR: Structure-based optimization was conducted to improve the potency, selectivity, and cell-based activities of β-catenin/B-cell lymphoma 9 (BCL9) inhibitors based on the 4'-fluoro- N-phenyl-[1,1'-biphenyl]-3-carboxamide scaffold, which was designed to mimic the side chains of the hydrophobic α-helical hot spots.
Journal ArticleDOI
Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals
TL;DR: Avoiding physical property descriptors that highlight dual BSEP and MDR3 inhibition or testing drug candidates for inhibition of multiple efflux transporters may be an effective strategy for prioritizing drug candidates with less likelihood of causing clinical DILI.
Journal ArticleDOI
preADMET analysis and clinical aspects of dogs treated with the Organotellurium compound RF07: A possible control for canine visceral leishmaniasis?
Adriana Maria Viana Nunes,Franscisco das Chagas Pereira de Andrade,Livia Alves Filgueiras,Octávio Augusto de Carvalho Maia,Rodrigo L. O. R. Cunha,Sindy V. A. Rodezno,Antônio Luiz Martins Maia Filho,Fernando Aécio de Amorim Carvalho,Débora Cavalcante Braz,Anderson Nogueira Mendes +9 more
TL;DR: The application of RF07 in the treatment of visceral leishmaniasis suggests that it is an alternative to the disease, since the reversal of clinical signs in dogs with VL requires the use of 0.6 mg/kg.
References
More filters
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.