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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Small Molecule Ghrelin Receptor Inverse Agonists and Antagonists
TL;DR: This review provides an overview of ghrelin biology with a focus on metabolic diseases and summarizes recent medicinal chemistry programs aimed at delivering small molecule ghrelIn receptor antagonists and inverse agonists to the clinic.
Journal ArticleDOI
Accelerating antibiotic discovery through artificial intelligence.
TL;DR: A review of AI-assisted advances in the discovery of both small molecule antibiotics and antimicrobial peptides is presented in this article, where the authors argue for openness and reproducibility as a means of accelerating preclinical research.
Journal ArticleDOI
Advances in drug discovery of new antitubercular multidrug-resistant compounds
TL;DR: Active compounds against MDR-TB with minimum inhibitory concentrations (MICs) less than 11 µM and low toxicity published in the last 4 years in the databases PubMed, Web of Science and Scopus will be presented and discussed.
Journal ArticleDOI
Iridium-Catalyzed Asymmetric Allylic Amination with Polar Amines: Access to Building Blocks with Lead-Like Molecular Properties
TL;DR: In this article, the combination of an air-stable iridium catalyst and the dipolar aprotic solvent dimethyl sulfoxide (DMSO) allowed the first systematic exploitation of highly polar, functionalized amines in asymmetric allylic substitutions: low molecular weight, sp 3 -rich chiral building blocks with physicochemical properties that will be valuable in the synthesis of lead-like small molecules.
Journal ArticleDOI
HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase.
Johan Evenäs,Fredrik Edfeldt,Matti Lepistö,Naila Svitacheva,Anna Synnergren,Britta Lundquist,Mia Gränse,Anna Rönnholm,M Varga,John Wright,Min Wei,Sherrie Yue,Junfeng Wang,Chong Li,Xuan Li,Gang Chen,Yong Liao,Gang Lv,Ann Tjörnebo,Frank Narjes +19 more
TL;DR: An NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts, and identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties.
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.