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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Truncated Nucleosides as A3 Adenosine Receptor Ligands: Combined 2-Arylethynyl and Bicyclohexane Substitutions
TL;DR: 4'-truncation of C2-arylethynyl-(N)-methanocarba adenosine derivatives is compatible with general preservation of A(3)AR selectivity, especially with small N(6) groups, but reduced efficacy in A( 3)AR-induced inhibition of adenylate cyclase.
Journal ArticleDOI
Nitro-substituted tetrahydroindolizines and homologs: Design, kinetics, and mechanism of α-glucosidase inhibition
Cinzia Tavani,Lara Bianchi,Annalisa De Palma,Giovanna Ilaria Passeri,Giuseppe Punzi,Ciro Leonardo Pierri,Angelo Lovece,Maria Maddalena Cavalluzzi,Carlo Franchini,Giovanni Lentini,Giovanni Petrillo +10 more
TL;DR: Kinetic analysis indicated that compound 3e is a mixed inhibitor with preference for the free enzyme over the α-glucosidase-substrate complex, and Circular dichroism spectroscopy studies suggested that the inhibition exerted by 3e may involve changes in the secondary structure of the enzyme.
Journal ArticleDOI
Molecular Topology Analysis of the Differences between Drugs, Clinical Candidate Compounds, and Bioactive Molecules
TL;DR: Differences in topology between drugs, clinical candidate compounds and bioactive molecules are highlighted and for most topological classes drugs have a lower RSC than the clinical candidates andBioactive molecules.
Journal ArticleDOI
Ligand-based virtual screening identifies a family of selective cannabinoid receptor 2 agonists.
Matteo Gianella-Borradori,Ivy Christou,Carole J. R. Bataille,Rebecca L. Cross,Graham Michael Wynne,David R. Greaves,Angela J. Russell +6 more
TL;DR: In this article, a ligand-based virtual screen was performed to identify selective CB2R agonists with appropriate physicochemical and ADME properties for future evaluation in vivo, and the most promising example, DIAS2, also showed favorable in vitro metabolic stability and absorption properties along with a clean selectivity profile when evaluated against a panel of GPCRs and kinases.
Journal ArticleDOI
Current Updates on Naturally Occurring Compounds Recognizing SARS-CoV-2 Druggable Targets.
TL;DR: In this article, a review aims to update on current status of the natural occurring compounds recognizing SARS-CoV-2 druggable targets, and some natural compounds are ongoing to examine their potential role to prevent and to treat the COVID-19 infection.
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.