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
Lipophilic efficiency: the most important efficiency metric in medicinal chemistry.
Journal ArticleDOI
Molecular Property Design: Does Everyone Get It?
Paul D. Leeson,Robert J. Young +1 more
TL;DR: Lead optimization trajectories aimed at reducing physicochemical risk, assisted by ligand efficiency metrics, could help to reduce clinical attrition rates.
Journal ArticleDOI
Lipophilic Permeability Efficiency Reconciles the Opposing Roles of Lipophilicity in Membrane Permeability and Aqueous Solubility
Matthew R. Naylor,Andrew M Ly,Mason J Handford,Daniel P Ramos,Cameron R. Pye,Akihiro Furukawa,Victoria G. Klein,Ryan P Noland,Quinn Edmondson,Alexandra C Turmon,William M. Hewitt,Joshua Schwochert,Chad E. Townsend,Colin N Kelly,Maria-Jesus Blanco,R. Scott Lokey +15 more
TL;DR: It is shown that LPE provides a functional assessment of the efficiency with which a compound achieves passive membrane permeability at a given lipophilicity, especially relevant to "beyond rule of 5" molecules.
Journal ArticleDOI
Properties of FDA-approved small molecule protein kinase inhibitors: A 2022 update
TL;DR: There are 68 FDA-approved therapeutic agents that target about two dozen different protein kinases and six of these drugs were approved in 2021 as discussed by the authors , including twelve target protein-serine/threonine protein kinase, four are directed against dual specificity MEK1/2, thirteen block nonreceptor protein-tyrosine protein-protein kinases, and 39 target receptor protein-synthesis kinases.
Journal ArticleDOI
Drug discovery: A question of library design
TL;DR: Two approaches have emerged for creating libraries of compounds for use in biological screening assays for drug discovery — fragment-based ligand design and diversity-oriented synthesis.
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.