Thyroid hormone receptor beta (THR-β), also known as nuclear receptor subfamily 1, group A, member 2 (NR1A2). Besides, it is a nuclear receptor protein that is encoded by the THRB gene in humans. In addition, THR-β is a receptor that binds thyroid hormone. Importantly, it plays an important role in many biological processes, such as metabolic regulation, neurodevelopment, cardiovascular function, etc. Moreover, THR-β has a transcriptional regulatory function, it can bind DNA and regulate the transcriptional activity of target genes, thereby affecting the growth and differentiation of cells. THR-β agonists can bind THR-β and activate its transcriptional regulation function. So, it plays role in treating hypothyroidism and other diseases related to abnormal thyroid hormone levels.

Resmetirom (MGL-3196) is a THR-β agonist for NASH research.

Resmetirom (MGL-3196) is a highly selective thyroid hormone receptor β (THR-β) agonist with an EC₅₀ value of 0.21 μM. In vitro studies, Resmetirom (MGL-3196) is 28-fold selective for THR-β ( EC₅₀=0.21 μM) over THR-α ( EC₅₀=3.74 μM ) in a functional assay. Resmetirom (MGL-3196) shows an IC₂₀ of roughly 30 μM for blockage of the hERG channel. The IC₅₀ for CYP3A4/5 and for CYP2C19 is >50 μM, and there is only weak inhibition (roughly 22 μM) of CYP2C9.

In vivo studies, Resmetirom (MGL-3196) exhibits good exposures and reasonable oral bioavailability in rats. The volume of distribution and clearance are both low. Dose proportional increases in exposure are observed for a suspension of Resmetirom (MGL-3196) given orally to DIO mice. In animals treated with Resmetirom (MGL-3196) there is a reduction in cholesterol and liver size, which is secondary to the reduction of liver TG. There is no effect on bone mineral density (BMD) or heart or kidney size in Resmetirom (MGL-3196) treated animals.

In conclusion, Resmetirom (MGL-3196) is a highly selective THR-β agonist for NASH research.

References:

[1] Martha J Kelly, et al.  J Med Chem. 2014 May 22;57(10):3912-23.

[2] Aimo Kannt, et al. Br J Pharmacol. 2021 Jun;178(12):2412-2423.