Thyroid receptor ligands. Part 2: Thyromimetics with improved selectivity for the thyroid hormone receptor beta

Area of Science:

• Medicinal Chemistry
• Molecular Pharmacology
• Structural Biology

Background:

• Thyroid hormone receptors (TRs) are crucial nuclear receptors regulating metabolism and development.
• TR-beta1 selective compounds are sought for therapeutic applications with reduced side effects.
• Existing thyromimetics often lack sufficient selectivity for TR subtypes.

Purpose of the Study:

• To design and synthesize novel thyromimetics with improved selectivity for TR-beta1.
• To investigate the structure-activity relationships (SAR) of these novel compounds.
• To elucidate the molecular interactions driving TR-beta1 selectivity.

Main Methods:

• Synthesis of thyromimetic compounds by modifying existing structures.
• Structure-activity relationship (SAR) studies to identify key structural features.
• X-ray crystallography to determine the complex structure of a potent ligand with TR-beta1 ligand-binding domain (LBD).

Main Results:

• Replacing the 3'-isopropyl group with bulkier substituents enhanced TR-beta1 selectivity.
• Compounds derived from structure 2, featuring a 3'-phenyl moiety with meta-positioned hydrophobic groups, were most potent and selective.
• X-ray data revealed that the bulky R3' phenyl ethyl amide side chain of compound 15c displaced methionine 442 in the TR-beta1 LBD.
• This displacement created an expanded binding pocket, accommodating the bulky side chain while maintaining full agonist activity.

Conclusions:

• Steric bulk at the 3' position is critical for achieving high TR-beta1 selectivity.
• The identified thyromimetics represent promising leads for TR-beta1 targeted therapies.
• Structural insights explain the mechanism of enhanced binding and selectivity through receptor pocket adaptation.