Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-α-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141

Based on the scaffold of the pharmacologically selective thyromimetic 2b, structurally a close analog to KB-141 (2a), a number of novel N-acylated-α-amino acid derivatives were synthesized and tested in a TR radioligand binding assay as well as in a reporter cell assay. On the basis of TRβ1-isoform selectivity and affinity, as well as affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.

Graphical abstractBased on the scaffold of the pharmacologically selective KB-141 (2a), N-acylated-α-amino acid derivatives were synthesized and tested in a TR-binding assay and a reporter cell assay. On the basis of TRβ1-isoform selectivity and affinity to the reporter cell assay, 3d was selected for further studies in the cholesterol-fed rat model. In this model 3d revealed an improved therapeutic window between cholesterol and TSH lowering but decreased margins versus tachycardia compared with 2a.Figure optionsDownload full-size imageDownload as PowerPoint slide