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

Abstract

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.

Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors

“…In the initial phase of our investigation, we conducted a retrospective evaluation of FMOScore’s performance concerning thyroid hormone receptor β (THR-β) agonists, using a set of 18 compounds taken from the work of Hu et al [ 65 ] ( Table S4 and Figure 5 A). Overall, we observed that the FMOScore approach ( R 2 = 0.71) exhibited a better correlation with Δ G exp compared to the FMO interaction energy ( R 2 = 0.46) ( Figure 5 C), which suggests that the solvation free energy and deformation energy contributions play a positive role in ligand binding.…”

Thyroid function, adipokines and mitokines in metabolic dysfunction‐associated steatohepatitis: A multi‐centre biopsy‐based observational study

“…58 The THRβ is a novel crucial target for NAFLD treatment as it regulates several hepatic metabolic pathways that have been related to NASH, and fibrosis development. 58 Selective THRβ agonists have high hepatic accumulation compared with their concentrations in the circulation, and thus, they could present fewer systemic adverse events while maximizing efficacy in the liver. 58 Preliminary results from clinical trials have shown promising outcomes for several THRβ selective agonists.…”

“…58 Selective THRβ agonists have high hepatic accumulation compared with their concentrations in the circulation, and thus, they could present fewer systemic adverse events while maximizing efficacy in the liver. 58 Preliminary results from clinical trials have shown promising outcomes for several THRβ selective agonists. In this context, a Phase 2 clinical trial of a THRβ agonist (Resmetirom) resulted in reduced liver fat content in patients with MASH without major side effects after 12 and 36 weeks of treatment.…”

Drug targets regulate systemic metabolism and provide new horizons to treat nonalcoholic steatohepatitis

“…The recent agonists exhibit advantages in THRα/β subtype selectivity. The only amino acid difference in ligand-binding pockets between THRα and THRβ accounts for the suboptimal subtype selectivity of previous THRβ agonists [ 67 ], thereby increasing the adverse effects in heart and bone by activation of THRα [ 68 ]. The optimized compounds are designed based upon the crystal structure between THRβ and the analog of MGL-3196.…”

“…The most potent compound undergoes two stages of optimization: In the first stage, the cyclization of MGL-3196 forms indole ring and exhibits 30-fold higher efficacy against THRβ, compared with MGL-3196 (EC 50 = 0.03 μM vs 0.99 μM of MGL-3196). In the second stage, the substitution on indole ring with N atom generates pyrrolo[3,2-b]pyridin-5-one skeleton, which yields much higher THRβ/α selectivity (11.2-fold vs 4.2-fold) and liver-to-serum ratio (93:1 vs 6:1) [ 68 ]. The single oral dose of new compound in murine model effectively lowers total cholesterol and LDL-cholesterol levels in serum.…”