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
Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties?
TL;DR: Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class.
Journal ArticleDOI
Automating drug discovery
TL;DR: This article aims to identify the approaches and technologies that could be implemented robustly by medicinal chemists in the near future and to critically analyse the opportunities and challenges for their more widespread application.
Journal ArticleDOI
Biophysical properties of the clinical-stage antibody landscape
Tushar Jain,Tingwan Sun,Stéphanie Durand,Amy L Hall,Nga Rewa Houston,Juergen Hermann Nett,Beth Sharkey,Beata Bobrowicz,Isabelle Caffry,Yao Yu,Yuan Cao,Heather Lynaugh,Michael G. Brown,Hemanta Baruah,Laura T. Gray,Eric Krauland,Yingda Xu,Maximiliano Vásquez,K. Dane Wittrup +18 more
TL;DR: This work attempts to quantify the historical limits of acceptability for multiple biophysical metrics of “developability" for essentially the full set of antibody drugs that have been tested in phase-2 or -3 clinical trials, or are approved by the FDA.
Journal ArticleDOI
Nanoparticle hydrophobicity dictates immune response.
Daniel F. Moyano,Meir Goldsmith,David J. Solfiell,Dalit Landesman-Milo,Oscar R. Miranda,Dan Peer,Vincent M. Rotello +6 more
TL;DR: Empirically engineered gold nanoparticles were used to determine the sole effect of hydrophobicity on the immune response of splenocytes, with an essentially linear increase in immune activity with the increase in hydrophOBicity observed in vitro.
Journal ArticleDOI
Probing the links between in vitro potency, ADMET and physicochemical parameters
TL;DR: Key findings include: first, that oral drugs seldom possess nanomolar potency; second, that many oral drugs have considerable off-target activity; and third, that in vitro potency does not correlate strongly with the therapeutic dose.
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.