Design and synthesis of a novel series of [1-(4-hydroxy-benzyl)-1H-indol-5-yloxy]-acetic acid compounds as potent, selective, thyroid hormone receptor β agonists

Burkholder, Timothy P.; Cunningham, Brian; Clayton, Joshua R.; Lander, Peter A.; Brown, Matthew L.; Doti, Robert A.; Durst, Gregory L.; Montrose‐Rafizadeh, Chahrzad; King, Constance; Osborne, Harold E.; Amos, Robert M.; Zink, Richard W.; Stramm, Lawrence E.; Burris, Thomas P.; Cardona, Guemalli R.; Konkol, Debra L.; Reidy, Charles; Christe, Michael E.; Génin, Michaël

doi:10.1016/j.bmcl.2015.02.062

Cited by 8 publications

(4 citation statements)

References 17 publications

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“…Previous studies report that the inherent binding mode constitutes a “His-Phe switch,” which means that the hydroxyl group of T3, His435 in helix 11 and Phe459 in helix 12 form a stable interaction and represent an inherent binding mode ( 24 ). However, TRβ1-H435R breaks His-Phe switch, resulting in insensitivity of the mutant for T3.…”

Section: Discussionmentioning

confidence: 99%

Resistance to Thyroid Hormone Beta Due to THRB Mutation in a Patient Misdiagnosed With TSH-Secreting Pituitary Adenoma

Liao,

Waisayanand,

Fanhchaksai

et al. 2024

JCEM Case Reports

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Elevated concentrations of T3 and T4 concomitant with nonsuppressed TSH are found in both TSH-producing tumors and resistance to thyroid hormone beta (RTHβ), posing a diagnostic challenge. We demonstrate here a 54-year-old female who presented with palpitations, goiter, and elevated free T4 with nonsuppressed TSH concentrations (TSH 2.2 mIU/L [normal range, NR 0.27-4.2 mIU/L] and FT4 59.08 pmol/L [NR 12.0-22.0 pmol/L]). Because magnetic resonance imaging revealed a pituitary microadenoma (4 mm), she was diagnosed with TSH-secreting pituitary adenoma and underwent transsphenoidal surgery. Pathological reports showed no tumor cells. Subsequent genetic testing revealed a pathogenic variant in the THRB gene resulting in a His435Arg amino acid substitution in the T3 receptor isoform beta 1 (TRβ1), suggestive of RTHβ. In vitro and ex vivo studies revealed that the His435Arg mutated TRβ1 (TRβ1-H435R) completely abolishes the T3-induced transcriptional activation, nuclear receptor corepressor 1 release, steroid receptor coactivator 1 recruitment, and T3-induced thyroid hormone target gene expression, confirming the pathogenicity of this variant. The identification of a pituitary microadenoma in a patient with RTHβ led to a misdiagnosis of a TSH-producing tumor and unnecessary surgery. Genetic testing proved pivotal for an accurate diagnosis, suggesting earlier consideration in similar clinical scenarios.

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Section: Discussionmentioning

confidence: 99%

Resistance to Thyroid Hormone Beta Due to THRB Mutation in a Patient Misdiagnosed With TSH-Secreting Pituitary Adenoma

Liao,

Waisayanand,

Fanhchaksai

et al. 2024

JCEM Case Reports

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“…THR-α and THR-β receptors differ by only a single amino acid in the ligand-binding site (Asn331 in THR-β versus Ser277 in THR-α), and triiodothyronine ( T3 , 1 , Figure ) has equal affinity for each subtype, which has made the development of selective ligands a challenge. Recently, several selective THR-β agonists have been developed − and two representative THR-β agonists VK2809 ( 2 ) and MGL-3196 ( 3 ) have progressed into clinical trials for the treatment of NASH. VK2809 ( 2 ) has no selectivity for THR-β but is liver-targeted via a prodrug strategy since the generation of its active form relies singularly on the action of CYP3A4 present in the liver. , Despite the highly selective cleavage mechanism, the active form of 2 is still detected in the plasma of rat, dog, and monkey .…”

Section: Introductionmentioning

confidence: 99%

Discovery of Highly Potent and Selective Thyroid Hormone Receptor β Agonists for the Treatment of Nonalcoholic Steatohepatitis

et al. 2023

J. Med. Chem.

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Nonalcoholic steatohepatitis (NASH) is a progressive stage of nonalcoholic fatty liver disease (NAFLD) and is characterized by steatosis, inflammation, hepatocyte ballooning, and fibrosis. While there are currently no approved therapies for NASH, the thyroid hormone receptor β (THR-β), primarily expressed in the liver, is emerging as an effective molecular target for the treatment of NASH. However, the adverse cardiac and bone effects mediated by thyroid hormone receptor α (THR-α) need to be minimized. Herein, we reported the discovery of a series of novel THR-β agonists featuring pyrrolo[3,2-b]pyridin-5-one skeletons based on structure-based drug design. Further optimization led to compound 15, which exhibited higher potency and selectivity for THR-β over THR-α compared to clinical drug MGL-3196. More significantly, an excellent liver-to-serum ratio of 93:1 was observed for compound 15. We believe that the high hepatic concentration of compound 15 may result in no cardiotoxicity.

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“…During the past two decades, most TRβ agonists bearing the inherent binding mode termed the “His-Phe switch” (Figure B) have been reported. ,− However, the mutation of TRβ, such as His435, will break the inherent His-Phe switch, resulting in the insensitivity of the thyroid hormone and most TRβ agonists. − Impaired sensitivity of TRβ to thyroid hormones leads to resistance to thyroid hormone (RTH), which is a syndrome characterized by tachycardia, goiter, and elevated serum thyroid hormone levels. − To date, only several agonists have been reported to activate the TRβ mutant. Koh’s group has successively found two compounds QH2 ( 6 , Figure ) and QH13 ( 7 , Figure ) that can maintain the activation on the H435A and H435Y mutations, respectively.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor β Agonist

Yao

Zhao

et al. 2022

J. Med. Chem.

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The design and development of agonists selectively targeting thyroid hormone receptor β (TRβ) and TRβ mutants remain challenging tasks. In this study, we first adopted the strategy of breaking the "His-Phe switch" to solve two problems, simultaneously. A structure-based design approach was successfully utilized to obtain compound 16g, which is a potent TRβ agonist (EC 50 : 21.0 nM, 85.0% of the maximum efficacy of 1) with outstanding selectivity for TRβ over TRα and also effectively activates the TRβ H435R mutant. Then, we developed a highly efficient synthetic method for 16g. Our serials of cocrystal structures revealed detailed structural mechanisms in overcoming subtype selectivity and rescuing the H435R mutation. 16g also showed excellent lipid metabolism, safety, metabolic stability, and pharmacokinetic properties. Collectively, 16g is a well-characterized selective and mutation-sensitive TRβ agonist for further investigating its function in treating dyslipidemia, nonalcoholic steatohepatitis (NASH), and resistance to thyroid hormone (RTH).

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Design and synthesis of a novel series of [1-(4-hydroxy-benzyl)-1H-indol-5-yloxy]-acetic acid compounds as potent, selective, thyroid hormone receptor β agonists

Cited by 8 publications

References 17 publications

Resistance to Thyroid Hormone Beta Due to THRB Mutation in a Patient Misdiagnosed With TSH-Secreting Pituitary Adenoma

Resistance to Thyroid Hormone Beta Due to THRB Mutation in a Patient Misdiagnosed With TSH-Secreting Pituitary Adenoma

Discovery of Highly Potent and Selective Thyroid Hormone Receptor β Agonists for the Treatment of Nonalcoholic Steatohepatitis

Discovery of a Highly Selective and H435R-Sensitive Thyroid Hormone Receptor β Agonist

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