Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules

Luker, Tim; Alcaraz, Lilian; Chohan, Kamaldeep K.; Blomberg, Niklas; Brown, David; Butlin, Roger J.; Elebring, Thomas; Griffin, Andrew M.; Guile, Simon D.; St-Gallay, Stephen A.; Swahn, Britt‐Marie; Swallow, Steve; Waring, Michael J.; Wenlock, Mark C.; Leeson, Paul D.

doi:10.1016/j.bmcl.2011.07.074

Cited by 54 publications

(36 citation statements)

References 25 publications

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“…1,2 In studies of extensive datasets of small molecules, the fundamental properties of molecular size, lipophilicity, shape and polarity have been correlated, to varying degrees, with solubility 3 , membrane permeability 4 , metabolic stability, 5,6 receptor promiscuity, 7 in vivo toxicity, 8,9 and attrition 10,11 in drug development pipelines.…”

Section: Introductionmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

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907

932

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Summary Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. For example, ligand efficiency, is the binding free energy per heavy atom count (LE = G/HA) and lipophilic ligand efficiency (LLE = pIC 50 or KicLogP/D). There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity. The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. In particular, optimisation of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging 'lipophile-preferring' targets. Mean ligand efficiency measures of molecules acting at a specific target, when combined with their drug-like physical properties, is a practical means of estimating target 'druggability.' This is exemplified with 480 targetassay pairs from the primary literature. Across these targets correlations between biological activity in vitro and physical properties are generally weak, showing that increasing activity by increasing physical properties is not always necessary. Charles H. ReynoldsCharles Reynolds is currently President of Gfree Bio, a modeling and structure-based design company in AbstractThe judicious application of ligand or binding efficiencies, which quantify the molecular properties required to gain binding affinity for a drug target, is gaining traction in the selection and optimisation of fragments, hits, and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimised ligand efficiency values for their target. Optimising ligand efficiencies based on both molecular size and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the molecular inflation that pervades current practice in medicinal chemistry, and to increase the developability of drug candidates.

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Section: Introductionmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

Self Cite

907

932

View full text Add to dashboard Cite

show abstract

“…Beginning with Lipinski's rule of five study 4 , initial studies focused on a link between physicochemical properties and the likelihood of attrition owing to poor absorption, distribution, metabolism and excretion (ADME) characteristics [4][5][6] . More recently, attention has focused on the influence of physicochemical properties on promiscuity 5,8 and in vivo toxicological outcomes 7,10 . It should, however, be noted that the manner in which analyses such as those in REFS 5,6 (and similar analyses) have been carried out has recently been criticized; in particular, critics have highlighted that the use of averaged or categorized (binned) data can exaggerate the strength of correlations 11 .…”

mentioning

confidence: 99%

“…Over the past two decades, multiple studies have proposed benefits (in terms of reduced likelihood of attrition) from controlling the physicochemical properties of compounds, such as size, lipophilicity and polarity, based on analyses of data sets of approved oral smallmolecule drugs and investigational compounds [4][5][6][7][8][9][10] . Beginning with Lipinski's rule of five study 4 , initial studies focused on a link between physicochemical properties and the likelihood of attrition owing to poor absorption, distribution, metabolism and excretion (ADME) characteristics [4][5][6] .…”

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confidence: 99%

An analysis of the attrition of drug candidates from four major pharmaceutical companies

Waring

Arrowsmith

Leach

et al. 2015

Nat Rev Drug Discov

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The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

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“…A closely related paper published in the same year by Ritchie and McDonald [17] came to similar conclusions based on a count of the number of aromatic rings in a molecule. A 2011 paper by Luker et al [18] used yet another method to quantitate 'flatness', and found that planar molecules have a significantly higher probability of failing in toxicology studies. In a 2011 paper, Leeson et al [7] propose the number of aromatic atoms minus the number of sp3 carbon atoms as an additional metric for 'aromatic balance'.…”

Section: Relationships Between Planarity and Drug-likenessmentioning

confidence: 98%

Going further than Lipinski's rule in drug design

Walters¹

2012

Expert Opinion on Drug Discovery

172

110

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While Lipinski's publication of the Ro5 and subsequent work by other authors has made medicinal chemists more aware of the relationships between physical properties and ADMET, it has hardly been a panacea. Pharmaceutical productivity continues to lag, and the industry is exploring new models to improve its output. If we are to progress, we need to move beyond simple models based on lipophilicity and gain a deeper understanding of molecular interactions.

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Strategies to improve in vivo toxicology outcomes for basic candidate drug molecules

Cited by 54 publications

References 25 publications

The role of ligand efficiency metrics in drug discovery

The role of ligand efficiency metrics in drug discovery

An analysis of the attrition of drug candidates from four major pharmaceutical companies

Going further than Lipinski's rule in drug design

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