Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

Cumming, John G.; Tucker, Howard; Oldfield, J.W.; Fielding, Colin; Highton, Adrian J.; Faull, Alan W.; Wild, Martin; Brown, David; Wells, Stuart L.; Shaw, John S.

doi:10.1016/j.bmcl.2011.12.117

Cited by 22 publications

(21 citation statements)

References 26 publications

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“…This can be accomplished by reducing lipophilicity in combination with structure-activity optimisation. 67 One of the most challenging targets of all in terms of obtaining drug-like physical properties is the cholesteryl ester transfer protein (CETP), 68 an atherosclerosis target where inhibition raises HDL-c levels. 69 65 Lipophilic efficiency parameters for agonists can be adjusted if required to take intrinsic activity into account.…”

Section: Application Of Efficiency Metrics In Optimisationmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

897

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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: Application Of Efficiency Metrics In Optimisationmentioning

confidence: 99%

The role of ligand efficiency metrics in drug discovery

Hopkins

Keserü

Leeson

et al. 2014

Nat Rev Drug Discov

897

View full text Add to dashboard Cite

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“…The representative CXCR4 ligands include compounds 31 , 80 32 , 154 33 – 34 , 155,156 35 , 157,187 36 , 158 and 37 ; 36 CCR5 ligands include compounds, 38 , 172 39 , 188 40 , 159 41 , 189 42 , 161 43 , 162 and 44 . 163 US28 ligands include compounds 45 , 180 46 , 47 , 181 48 , 182 49 , 181 50 , 184 51 , 185 and 52 .…”

Section: Crystal Structure-based Analysis Of the Effects Of Site-dirementioning

confidence: 99%

Structural Analysis of Chemokine Receptor–Ligand Interactions

et al. 2017

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This review focuses on the construction and application of structural chemokine receptor models for the elucidation of molecular determinants of chemokine receptor modulation and the structure-based discovery and design of chemokine receptor ligands. A comparative analysis of ligand binding pockets in chemokine receptors is presented, including a detailed description of the CXCR4, CCR2, CCR5, CCR9, and US28 X-ray structures, and their implication for modeling molecular interactions of chemokine receptors with small-molecule ligands, peptide ligands, and large antibodies and chemokines. These studies demonstrate how the integration of new structural information on chemokine receptors with extensive structure–activity relationship and site-directed mutagenesis data facilitates the prediction of the structure of chemokine receptor–ligand complexes that have not been crystallized. Finally, a review of structure-based ligand discovery and design studies based on chemokine receptor crystal structures and homology models illustrates the possibilities and challenges to find novel ligands for chemokine receptors.

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“…Alternately, lowering the lipophilicity of drugs, by including polar substituents for instance, was also demonstrated as an effective strategy to reduce the affinity of the drug toward the lipophilic cavity of the hERG channel 46,140,147,156 . For example, Cumming et al 30 optimized 1-(3,3-diphenylpropyl)-piperidine phenylacetamide, a CCR5 antagonist, to reduce their affinity toward hERG by reducing the lipophlicity of the compound. They substituted an aromatic ring of diphenylpropyl moiety with saturated heterocyclic rings, such as piperazine and piperidine to reduce the lipophilicity of the compound by ß1 unit.…”

Section: Small Molecule Optimization For Herg Activitymentioning

confidence: 99%

Development of Safe Drugs: The hERG Challenge

Kalyaanamoorthy

Barakat

2017

Medicinal Research Reviews

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Drug-induced blockade of human ether-a-go-go-related gene (hERG) remains a major impediment in delivering safe drugs to the market. Several drugs have been withdrawn from the market due to their severe cardiotoxic side effects triggered by their off-target interactions with hERG. Thus, identifying the potential hERG blockers at early stages of lead discovery is fast evolving as a standard in drug design and development. A number of in silico structure-based models of hERG have been developed as a low-cost solution to evaluate drugs for hERG liability, and it is now agreed that the hERG blockers bind at the large central cavity of the channel. Nevertheless, there is no clear convergence on the appropriate drug binding modes against the channel. The proposed binding modes differ in their orientations and interpretations on the role of key residues in the channel. Such ambiguities in the modes of binding remain to be a significant challenge in achieving efficient computational predictive models and in saving many important already Food and Drug Administration approved drugs. In this review, we discuss the spectrum of reported binding modes for hERG blockers, the various in silico models developed for predicting a drug's affinity to hERG, and the known successful optimization strategies to avoid off-target interactions with hERG.

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Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

Cited by 22 publications

References 26 publications

The role of ligand efficiency metrics in drug discovery

The role of ligand efficiency metrics in drug discovery

Structural Analysis of Chemokine Receptor–Ligand Interactions

Development of Safe Drugs: The hERG Challenge

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