Structure-effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination

Ha, Huy Riêm; Stieger, Bruno; Grassi, G.; Altorfer, Hans; Folláth, Ferenc

doi:10.1007/s002280050701

Cited by 34 publications

(17 citation statements)

References 24 publications

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“…This compound was prepared with a yield of 60% as described previously (Ha et al, 2000). Melting point (146.4 -146.9°C) and NMR data (not shown) were in agreement with the previous report.…”

Section: Chemistry and General Methodssupporting

confidence: 87%

“…All the amiodarone metabolites or derivatives used were synthesized from B2. B2 was synthesized as described previously (Ha et al, 2000). The derivatives B2-O-Et-NH-ethyl, B2-O-Et-NH 2 , B2-O-Et-N-dimethyl, and B2-OEt-N-dipropyl were prepared by condensing B2 with the respective 2-chloroethyl amine hydrochloride salts in the presence of K 2 CO 3 .…”

Section: Synthesis Of B2-o-et-nh-ethylmentioning

confidence: 99%

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Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

Waldhauser

Török

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

108

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The aim of this work was to compare hepatocellular toxicity and pharmacological activity of amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran; B2-O-Et-Ndiethyl) and of eight amiodarone derivatives. Three amiodarone metabolites were studied, namely, mono-N-desethylamioda- A concentration-dependent increase in lactate dehydrogenase leakage from HepG2 cells and isolated rat hepatocytes was observed in the presence of amiodarone and of most analogs, confirming their hepatocellular toxicity. Using freshly isolated rat liver mitochondria, amiodarone and most analogs showed a dose-dependent toxicity on the respiratory chain and on ␤-oxidation, significantly reducing the respiratory control ratio and oxidation of palmitate, respectively. The reactive oxygen species concentration in hepatocytes increased time-dependently, and apoptotic/necrotic cell populations were identified using flow cytometry and annexin V/propidium iodide staining. The effect of the three least toxic amiodarone analogs on the human ether-a-go-go-related gene (hERG) channel was compared with amiodarone. Amiodarone, B2-O-acetate, and B2-O-Et-N-dipropyl (each 10 M) significantly reduced the hERG tail current amplitude, whereas 10 M B2-O-Et displayed no detectable effect on hERG outward potassium currents. In conclusion, three amiodarone analogs (B2-O-Et-N-dipropyl, B2-O-acetate, and B2-O-Et) showed a lower hepatocellular toxicity profile than amiodarone, and two of these analogs (B2-O-Et-Ndipropyl and B2-O-acetate) retained hERG channel interaction capacity, suggesting that amiodarone analogs with class III antiarrhythmic activity and lower hepatic toxicity could be developed.

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Section: Chemistry and General Methodssupporting

confidence: 87%

Section: Synthesis Of B2-o-et-nh-ethylmentioning

confidence: 99%

Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

Waldhauser

Török

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

108

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“…A Friedel–Crafts acylation next introduces the aryl ring at the 3-position. Demethylation, iodination and a final alkylation with a diethylaminoethane fragment yields amiodarone [115–117]. …”

Section: Reviewmentioning

confidence: 99%

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Baumann¹,

Baxendale²,

Ley³

et al. 2011

Beilstein J. Org. Chem.

503

269

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SummaryThis review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.

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“…This concept remains, however, largely to be established as several alternative mechanisms have been proposed to explain the hypothyroid-like action of the agents mentioned above. It has been showed that 10 may inhibit peripheral conversion of 2 to 1 through interaction with deiodinases [69,70], inhibit cellular uptake of 2 and/or 1 [71] or act directly on the on the cardiac contractility.…”

Section: Debated Mechanism Of Action: Amiodarone and Its Structural Amentioning

confidence: 99%

Thyroid Hormone Antagonists: Potential Medical Applications and Structure Activity Relationships

Malm¹,

Färnegårdh²,

Grover³

et al. 2009

CMC

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Thyroid hormone receptors (TRs) exert profound effects on development, metabolism, and multiple specific organ functions. Principally by regulating crucial genes in a variety of tissues, the thyroid hormones, 3,5,3'-triiodo-L-thyronine (L-T(3), 1) and 3,5,3',5'-tetraiodo-L-thyronine (L-T(4), 2), influence basal calorigenesis and oxygen consumption, cardiac rate and contractility, lipid metabolism, bone structure and strength, and central nervous system functions critical for normal mentation and mood. Elevated levels of circulating and tissue 1 and/or 2 result in the thyrotoxic clinical state, manifested by weight loss despite increased caloric intake; heat intolerance due to increased calorigenesis; cardiac tachyarrhythmias, systolic hypertension, and heart failure; skeletal muscle weakness; and a spectrum of neuropsychiatric symptoms ranging from anxiety to delirium and psychosis. The current standard treatments of endogenous hyperthyroidism causing thyrotoxicosis reduce the overproduction of thyroid hormones by pharmacologically inhibiting their synthesis or release (e.g., with thionamides or lithium, respectively), or by ablating thyroid tissue surgically or with radioiodine. TR-antagonists could hypothetically have significant clinical use in treating thyrotoxic states if they were capable of promptly and completely restoring euthyroid levels of thyroid-specific gene activity. No TRalpha-selective ligands have been prepared up to this date, ligands that potentially would further ameliorate the problem with cardiac disease connected with hyperthyroidism and maybe cardiac arrhythmia. Despite its significant potential use, no TR-antagonist has reached clinical application. Design of TR-antagonists ligands has been based on the attachment of a large extension group at the 5-prime position of 1 or other structurally related analogues. This extension is believed to distort folding of the C-terminal helix (helix 12) to the body of the ligand binding domain (LBD), which normally forms a coactivator site. Examples of synthetic TR antagonists based on this extension strategy are reviewed, as well as other strategies to achieve functional TR-antagonism.

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Structure-effect relationships of amiodarone analogues on the inhibition of thyroxine deiodination

Abstract: It is likely that the degraded products of AMI could be responsible for thyroid dysfunction toxicosis in AMI therapy.

Cited by 34 publications

References 24 publications

Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Thyroid Hormone Antagonists: Potential Medical Applications and Structure Activity Relationships

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