Abstract
Introduction: We have previously shown that administration of thyroid hormone and its analogue, sobetirome, attenuated bleomycin-induced lung fibrosis.
Objective: To design, develop and implement novel Thyroid Receptor beta (TRβ) agonists (thyromimetics) in experimental models of lung fibrosis.
Methods and results: The concept of bioisosterism was applied. In particular, the carboxylic acid of sobetirome was replaced by two different structural motifs, the boronic acid and the 2,6-difluorophenol group. Six new Sobetirome bioisosteres have been synthesized and characterized. 3D chrystalography revealed that two of the new bioisosteres exhibited higher affinity with a Met442 residue within the active center of the ΤRβ. Subsequently, the drug-like properties (aqueous solubility, cell membrane permeability, cytotoxicity, cardiotoxicity) of the 2 best analogue(s) were evaluated using ADMET assays. These two derivatives exhibited agonistic properties for ΤRβ, as assessed by Human ΤRβ reporter assay system (Indigo Biosciences). One derivative was then administered orotracheally in 9-12 weeks-old C57/BL6 mice at days 10-12 following bleomycin injury (2.5 IU) at a dose of 10mg/kg. Administration of thyromimetic was associated with significant attenuation of bleomycin-induced fibrosis as assessed by reduced hydroxyproline levels (133 + 34 και 142+29 vs 225+45 ug/gr, p<0.001) and Masson trichrome staining compared to controls.
Conclusions: Our study devised two novel thyromimetics with agonistic properties for ΤRβ and in-vivo therapeutic activity against bleomycin-induced lung injury. Thyromimetics may hold therapeutic promise for pulmonary fibrosis.
Footnotes
Cite this article as: European Respiratory Journal 2021; 58: Suppl. 65, OA4334.
This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.
This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).
- Copyright ©the authors 2021