Design, synthesis and docking study of novel series of thyromimetics for the treatment of MASLD

Metabolic-dysfunction Associated Steatotic Liver Disease (MASLD), formerly known as Non-Alcoholic Fatty Liver Disease (NAFLD), is a spectrum of liver pathologies, characterized by abnormal fat accumulation within hepatocytes, which could lead to liver damage, inflammation (Metabolic-dysfunction Associated Steatohepatitis - MASH) and, eventually, hepatocellular carcinoma (HCC). Thyroid hormones (THs), thyroxine - T4 – and 3,5,3’-triiodothyronine – T3, the physiologically active form - interact with thyroid hormone receptor (THR) found in two different isoforms, α and β, whose stimulation exerts radically different effects. THR-α activation mainly leads to cardiac effects, such as cardiac hypertrophy, tachycardia, arrhythmias, as well as muscle and bone catabolism. Conversely, THR-β activation elicits raised hepatic lipid metabolism, associated to a decrease of hepatocyte fat concentration. Hence, exploiting the above-mentioned isoform duality, by developing strictly β-selective thyromimetics, could unquestionably offer beneficial effects on MASLD. The diarylmethane compound TG68 and its bioactive form IS25, have demonstrated selective THR-β agonism 1. In this work, we report the synthesis and the computational studies of a new series of diarylmethane derivatives synthesized replacing the carboxylic acid moiety with different bioisosters. The activities (EC₅₀) against both isoforms were measured by means of LanthaScreen™ TR-FRET Nuclear Receptor Coregulator Assay. Herein the synthesis of novel diarylmethane compounds together with the in vitro activities (EC₅₀) are presented and discussed. Moreover, the engagement of the novel compounds with both THR isoforms was investigated. References [1] Caddeo A, Kowalik MA, Serra M, Runfola M, Bacci A, Rapposelli S, Columbano A, Perra A., TG68, a Novel Thyroid Hormone Receptor-β Agonist for the Treatment of NAFLD., Int J Mol Sci.,2021 Dec 3;22(23):13105.