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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Design, Synthesis, and Physicochemical and Pharmacological Profiling of 7-Hydroxy-5-oxopyrazolo[4,3-b]pyridine-6-carboxamide Derivatives with Antiosteoarthritic Activity In Vivo.
Claudia Mugnaini,Magdalena Kostrzewa,Marta Bryk,Ali M. Mahmoud,Antonella Brizzi,Stefania Lamponi,Gianluca Giorgi,Francesca Ferlenghi,Federica Vacondio,Paola Maccioni,Giancarlo Colombo,Marco Mor,Katarzyna Starowicz,Vincenzo Di Marzo,Alessia Ligresti,Federico Corelli +15 more
TL;DR: Among them, compound 51 emerged as a potent CB2R agonist able to reduce pain in rats carrying OA induced by injection of monoiodoacetic acid (MIA).
Journal ArticleDOI
Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B.
Kasi Viswanatharaju Ruddraraju,Devesh Aggarwal,Congwei Niu,Erica Anne Baker,Ruo-Yu Zhang,Li Wu,Zhong Yin Zhang +6 more
TL;DR: Kinetic, molecular docking, and site-directed mutagenesis analyses confirmed N-phenyl oxamic acid as a highly potent and selective monoacid-based phosphotyrosine mimetic for mPTPB inhibition and these compounds can reverse the altered host cell immune responses induced by the bacterial phosphatase.
Journal ArticleDOI
Collaboration versus outsourcing: the need to think outside the box.
TL;DR: Current outsourcing and collaboration strategies are reviewed to provide a perspective on how great knowledge sharing could help revise the drug-discovery process and, thus, move towards a more genuine collaborative process.
Journal ArticleDOI
Pyrimidone-based series of glucokinase activators with alternative donor-acceptor motif.
Kevin J. Filipski,Angel Guzman-Perez,Jianwei Bian,Christian Perreault,Gary Erik Aspnes,Mary Theresa Didiuk,Robert L. Dow,Richard F. Hank,Christopher S. Jones,Robert John Maguire,Meihua Tu,Dongxiang Zeng,Shenping Liu,John D. Knafels,John Litchfield,Karen Atkinson,David R. Derksen,Francis Bourbonais,Ketan S. Gajiwala,Michael J. Hickey,Theodore O. Johnson,Paul S. Humphries,Jeffrey A. Pfefferkorn +22 more
TL;DR: It is demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent and may find utility in other glucokinase activator series or beyond.
Journal ArticleDOI
Synthesis, cytotoxicity and DNA binding of oxoazabenzo[de]anthracenes derivatives in colon cancer Caco-2 cells.
TL;DR: The results confirm that the presence of the oxoazabenzo[de]anthracenes together with the piperidino functionality is crucial in exerting DNA binding and cytotoxic properties, hence demonstrating promise as a chemical scaffold for further development of new anticancer agents.
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.