Medicinal Chemistry of hERG Optimizations:  Highlights and Hang-Ups

Jamieson, Craig; Moir, Elizabeth M.; Rankovic, Zoran; Wishart, Grant

doi:10.1021/jm060379l

Cited by 383 publications

(370 citation statements)

References 75 publications

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“…Although the mode of action has not been fully elucidated, experimental evidence supports their binding to the inner pore of voltage-gated sodium channels (68 -70). The ion channel activity of ␤-aminoketones is related to the basic tertiary amine moiety (71,72). Although we successfully reduced the hERG activity of this series by the manipulation of the amine pK a (34), they still exhibit ion channel binding.…”

Section: Discussionmentioning

confidence: 99%

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Hwang

Huang

Arnold

et al. 2011

Journal of Biological Chemistry

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Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor (NR) superfamily and regulate development, growth, and metabolism. Upon binding thyroid hormone, TR undergoes a conformational change that allows the release of corepressors and the recruitment of coactivators, which in turn regulate target gene transcription. Although a number of TR antagonists have been developed, most are analogs of the endogenous hormone that inhibit ligand binding. In a screen for inhibitors that block the association of TR␤ with steroid receptor coactivator 2 (SRC2), we identified a novel methylsulfonylnitrobenzoate (MSNB)-containing series that blocks this interaction at micromolar concentrations. Here we have studied a series of MSNB analogs and characterized their structure activity relationships. MSNB members do not displace thyroid hormone T 3 but instead act by direct displacement of SRC2. MSNB series members are selective for the TR over the androgen, vitamin D, and PPAR␥ NR members, and they antagonize thyroid hormone-activated transcription action in cells. The methylsulfonylnitro group is essential for TR␤ antagonism. Side-chain alkylamine substituents showed better inhibitory activity than arylamine substituents. Mass spectrum analysis suggested that MSNB inhibitors bind irreversibly to Cys-298 within the AF-2 cleft of TR␤ to disrupt SRC2 association.

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Section: Discussionmentioning

confidence: 99%

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Hwang

Huang

Arnold

et al. 2011

Journal of Biological Chemistry

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“…[8] This potential for QT prolongation has led to severe restriction or withdrawal of several medications from the market. Intense efforts are directed at gaining a better understanding of the molecular basis of hERG channel blockade, including in vivo, in vitro, and in silico approaches (for a review, see reference [9]). Several groups have presented homology models of the hERG pore domain, providing a qualitative insight into potential ligand-channel interactions (for examples, see references [10][11][12][13][14]), and in some cases quantitative predictions have been provided.…”

Section: Introductionmentioning

confidence: 99%

Toward a Consensus Model of the hERG Potassium Channel

et al. 2010

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Malfunction of hERG potassium channels, due to inherited mutations or inhibition by drugs, can cause long QT syndrome, which can lead to life-threatening arrhythmias. A three-dimensional structure of hERG is a prerequisite to understand the molecular basis of hERG malfunction. To achieve a consensus model, we carried out an extensive analysis of hERG models based on various alignments of helix S5. We analyzed seven models using a combination of conventional geometry/packing/normality validation methods as well as molecular dynamics simulations and molecular docking. A synthetic test set with the X-ray crystal structure of K(v)1.2 with artificially shifted S5 sequences modeled into the structure served as a reference case. We docked the known hERG inhibitors (+)-cisapride, (S)-terfenadine, and MK-499 into the hERG models and simulation snapshots. None of the single analyses unambiguously identified a preferred model, but the combination of all three revealed that there is only one model that fulfils all quality criteria. This model is confirmed by a recent mutation scanning experiment (P. Ju, G. Pages, R. P. Riek, P. C. Chen, A. M. Torres, P. S. Bansal, S. Kuyucak, P. W. Kuchel, J. I. Vandenberg, J. Biol. Chem. 2009, 284, 1000-1008). We expect the modeled structure to be useful as a basis both for computational studies of channel function and kinetics as well as the design of experiments.

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“…While correlations are expected to be weak for a large set of diverse compounds, a strategy to modulate pK a may be more successful on a specific scaffold or series (reviewed in [26]). It should be noted that other factors such as lipophilicity are important in modulating hERG inhibition [27], as exemplified in the next section.…”

mentioning

confidence: 99%

Recent Advances in Physicochemical and ADMET Profiling in Drug Discovery

Wang

Skolnik

2009

Chemistry & Biodiversity

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The drastic increase in the cost for discovering and developing a new drug along with the high attrition rate of development candidates led to shifting drug-discovery strategy to parallel assessment of comprehensive drug physicochemical, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties alongside efficacy. With the proposal of a profiling paradigm and utilization of integrated risk assessment, one can exponentially enhance the predictive power of in vitro tools by taking into consideration the interplay among profiling parameters. In particular, this article will review recent advances in accurate assessment of solubility and other physicochemical parameters. The proper interpretation of these experimental data is crucial for rapid and meaningful risk assessment and rational optimization of drug candidates in drug discovery. The impact of these tools on assisting drug-discovery teams in establishing in vitro-in vivo correlation (IVIVC) as well as structure-property relationship (SPR) will be presented.

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Medicinal Chemistry of hERG Optimizations: Highlights and Hang-Ups

Cited by 383 publications

References 75 publications

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Methylsulfonylnitrobenzoates, a New Class of Irreversible Inhibitors of the Interaction of the Thyroid Hormone Receptor and Its Obligate Coactivators That Functionally Antagonizes Thyroid Hormone

Toward a Consensus Model of the hERG Potassium Channel

Recent Advances in Physicochemical and ADMET Profiling in Drug Discovery

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