Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc

Price, David A.; Armour, Duncan; Groot, Marcel de; Leishman, Derek J.; Napier, Carolyn; Perros, Manos; Stammen, Blanda; Wood, Anthony

doi:10.1016/j.bmcl.2006.06.012

Cited by 69 publications

(40 citation statements)

References 9 publications

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“…Price and co-workers [57] recently detailed their work on overcoming hERG liability in the discovery of HIV antiinfective maraviroc, a CCR5 antagonist. The initial drop in hERG binding was achieved by switching from benzimidazole to a less lipophilic alkyltriazole, and hERG blockade was finally eliminated when difluorocyclohexyl was used in place of cyclobutyl in the amide capping group (Fig.…”

Section: A Reducing Lipophilicitymentioning

confidence: 98%

Ligand Structural Aspects of hERG Channel Blockade

Aronov

2008

CTMC

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Sudden death as a side effect of action of non-antiarrhythmic drugs is a major pharmacological safety concern facing the pharmaceutical industry and the health regulatory authorities. A number of drugs have been withdrawn from the market in recent years due to cardiovascular toxicity associated with undesirable blockade of hERG potassium channel. Pharmaceuticals of widely varying structure have been shown to interact with hERG. Defining the molecular features that confer hERG inhibitory activity has therefore become a focus of considerable computational and statistical modeling efforts. Some of the approaches are aimed primarily at filtering out potential hERG blockers in the context of virtual libraries, while others involve understanding structure-activity relationships governing hERG-drug interactions. The ability of models to produce structural hypotheses that can be tested by the project teams has become the key prerequisite driving their organization-wide adoption.

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Section: A Reducing Lipophilicitymentioning

confidence: 98%

Ligand Structural Aspects of hERG Channel Blockade

Aronov

2008

CTMC

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“…Reproduced with permission from Rockefeller Press [43]. vanced strategies to measure and avoid nonhydrophobic interactions of CKR antagonists with the hERG channel can help select agents with decreased risk of cardiac complications [120,121]. Fig.…”

Section: Ckr Antagonist Selectivitymentioning

confidence: 99%

Chemokine Receptors as Targets for Cancer Therapy

Lee

Chevalier

et al. 2009

CPD

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Chemokines and their receptors play critical roles in leukocyte trafficking during inflammatory processes. Although the role of chemokine receptors (CKRs) in cancer biology is a relatively new field of study, a growing body of data suggest that a number of CKRs, including CXCR4, CCR4, CCR7, and CCR10, may play diverse of roles in cancer growth, cancer metastasis, cancer angiogenesis, or the composition of the cancer microenvironment. Preclinical models of cancer indicate that cancer antagonists, most notably those for CXCR4, can block cancer growth either directly or by altering the cancer stroma. Highthroughput screening methods to identify effective CKR antagonists have been developed, but specificity, potency, and drug-delivery of validated candidate compounds remain issues that result in the clinical failure of many initially promising candidates. The recent approval of a CCR5 receptor antagonist in HIV suggests that safe, effective small molecular antagonists for other CKRs may not be far away. There is still a clear need to extend our understanding of the signalling pathways by which CKRs facilitate cancer processes. Because of the role of CKRs in cancer cell survival, the combination of CKR antagonists with traditional chemotoxic agents or with immunotherapy is an alluring strategy since this increases the specificity of treatment to the cancer and potentially limits additional systemic side effects.

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“…Whereas the discovery process of Maraviroc revealed that both of the difluorocyclohexyl moiety and the exo -1,2,4-triazole substituted tropane core are essential to its potent antiviral activity and weak hERG inhibition. 35 Additionally, an interactive docking study of Maraviroc to a rhodopsin-based CCR5 homology model demonstrated the interactions between Glu283 and the tropane core, as well as Ile198 and the difluorocyclohexyl moiety within the proposed binding pocket. 36 Hence, the para -position of the phenyl ring in Maraviroc was first chosen as the linking site to avoid severe impacts to the above interactions.…”

Section: Bivalent Ligand Rational Designmentioning

confidence: 98%

Design and synthesis of a bivalent ligand to explore the putative heterodimerization of the mu opioid receptor and the chemokine receptor CCR5

et al. 2012

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The bivalent ligand approach has been utilized not only to study the underlying mechanism of G protein-coupled receptors dimerization and/or oligomerization, but also aimed to enhance ligand affinity and/or selectivity for potential treatment of a variety of diseases by targeting this process. Substance abuse and addiction have made both the prevention and the treatment of human immunodeficiency virus (HIV) infection more difficult to tackle. It has been extensively studied that morphine, a mu opioid receptor (MOR) agonist, can accelerate HIV infection through up-regulating the expression of the chemokine receptor CCR5, a well-known co-receptor for HIV invasion to the host cells. Meanwhile, two research groups have described the putative MOR/CCR5 heterodimers in their independent studies. The purpose of this paper is to report the design and synthesis of a bivalent ligand to explore the biological and pharmacological process of the putative MOR/CCR5 dimerization phenomenon. The developed bivalent ligand thus contains two distinct pharmacophores linked through a spacer; ideally one of which will interact with the MOR and the other with the CCR5. Naltrexone and Maraviroc were selected as the pharmacophores to generate such a bivalent probe. The overall reaction route to prepare this bivalent ligand was convergent and efficient, and involved sixteen steps with moderate to good yields. The preliminary biological characterization showed that the bivalent compound 1 retained the pharmacological characteristics of both pharmacophores towards the MOR and the CCR5 respectively with relatively lower binding affinity, which tentatively validated our original molecular design.

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Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc

Cited by 69 publications

References 9 publications

Ligand Structural Aspects of hERG Channel Blockade

Ligand Structural Aspects of hERG Channel Blockade

Chemokine Receptors as Targets for Cancer Therapy

Design and synthesis of a bivalent ligand to explore the putative heterodimerization of the mu opioid receptor and the chemokine receptor CCR5

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