Structure activity relationships of thyroxine analogs

Jorgensen, Eugéne C.

doi:10.1016/0306-039x(76)90073-8

Cited by 12 publications

(21 citation statements)

References 77 publications

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“…With such a small chemical alteration differentiating prodrug from parent drug, it is necessary to characterize prodrug activity at the thyroid hormone receptor (TR) target. Prior thyromimetic SAR suggests it is important to have an anionic carboxylate at this position for high-affinity TR binding . In cellular transactivation assays with either human TRα or human TRβ, Sob-AM2 was found to have weak agonist activity that was less potent than that of either sobetirome or T3 (Figure , Table S2).…”

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confidence: 98%

“…Prior thyromimetic SAR suggests it is important to have an anionic carboxylate at this position for high-affinity TR binding. 28 In cellular transactivation assays with either human TRα or human TRβ, Sob-AM2 was found to have weak agonist activity that was less potent than that of either sobetirome or T3 (Figure 4, Table S2). Because Sob-AM2-induced TR activation decreased at higher concentrations creating a bell-shaped profile, it is not clear whether this is partial agonist activity or agonist activity blunted by cytotoxicity at high Sob-AM2 concentrations.…”

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confidence: 99%

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Structure–Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs

Meinig

Ferrara

Banerji

et al. 2018

ACS Med. Chem. Lett.

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Thyroid hormone (TH) action is of clinical interest in treating demyelinating diseases of the central nervous system (CNS). Two amide prodrugs of sobetirome, a potent thyroid hormone agonist, were previously shown to significantly improve CNS selective distribution of the parent drug through hydrolysis in the CNS by fatty acid amide hydrolase (FAAH). This concept is elaborated upon here with a series of 29 amide prodrugs targeting FAAH. We identify that conservative aliphatic modifications such as the N-methyl (4), N-ethyl (5), N-fluoroethyl (15), and N-cyclopropyl (18) substantially favor selective CNS distribution of the parent drug in mice. Additionally, lead compounds exhibit moderate to good rates of hydrolysis at FAAH in vitro suggesting both enzymatic and physicochemical properties are important parameters for optimization. Both 4 and 15 were orally bioavailable while retaining appreciable CNS parent drug delivery following an oral dose. The pharmacokinetic parameters of 4 over 24 h postdose (i.v. and p.o.) were determined.

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confidence: 98%

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confidence: 99%

Structure–Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs

Meinig

Ferrara

Banerji

et al. 2018

ACS Med. Chem. Lett.

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“…An interesting characteristic of the structure of thyroid hormones is the mutual perpendicularity of the tyrosyl ring and phenolic ring. This unique conformation of the diphenyl ether linkage is important for the biological activity of T4. , The two torsional angles, φ and φ′ (Figure A), appear to control the perpendicular arrangement of the phenolic and tyrosyl rings, with one iodine atom in the phenolic ring occupying a position close to the tyrosyl ring in T4.…”

Section: Resultsmentioning

confidence: 99%

Conformational Flexibility and Halogen Bonding in Thyroid Hormones and Their Metabolites

Mondal

Mugesh

2016

Crystal Growth & Design

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Iodothyronamines (TAMs) are endogenous thyroid hormone (TH) metabolites, which are proposed to be biosynthesized by decarboxylation of the β-alanine side chain of THs. Iodothyronine deiodinases (DIOs) mediate phenolic and tyrosyl ring deiodinations of thyroid hormones and play an important role in thyroid hormone homeostasis. These enzymes also accept iodothyronamines as substrates for deiodination, but the binding affinities of TAMs to DIOs are lower than that of THs. In this paper, we report, for the first time, the formation of halogen bonding in various iodothyronamines by using single crystal X-ray studies. We also describe the conformational changes that take place in the structures of THs and TAMs upon deiodination. Density functional theory calculations were performed to understand the halogen bonded assembly and their biological implications.

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“…The main structural requirements for thyromimetic activity can be summarized as follows (6,(12)(13)(14)(15)(16). (1) Two aromatic rings insulated electronically from each other by connecting oxygen, sulfur, or carbon bridges, forming a central lipophilic core in which the two rings are angled 120 • .…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Thyroid and Antithyroid Preparations

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The main role of the human thyroid gland is the production of thyroid hormones, essential for adequate growth, development, and energy metabolism. Thyroid underfunction can be treated successfully with thyroid preparations. Thyroid hyperfunction can be corrected by treatment with antithyroid drugs. Thyromimetic compounds and antithyroid substances are discussed. Calcitonin, a hypercalcemic hormone, is also found in the thyroid gland, and its characteristics are investigated. Commercial preparation and prices of thyroid and antithyroid preparations are provided.

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Structure activity relationships of thyroxine analogs

Cited by 12 publications

References 77 publications

Structure–Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs

Structure–Activity Relationships of Central Nervous System Penetration by Fatty Acid Amide Hydrolase (FAAH)-Targeted Thyromimetic Prodrugs

Conformational Flexibility and Halogen Bonding in Thyroid Hormones and Their Metabolites

Thyroid and Antithyroid Preparations

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