Author/Authors :
Neeraj Garg، نويسنده , , Yi-Lin Li، نويسنده , , Ana Maria Garcia Collazo، نويسنده , , Chris Litten، نويسنده , , Denis E. Ryono، نويسنده , , Minsheng Zhang، نويسنده , , Yolanda Caringal، نويسنده , , Robert P. Brigance، نويسنده , , Wei Meng، نويسنده , , William N. Washburn، نويسنده , , Peter Agback، نويسنده , , Karin Mellstr?m، نويسنده , , Stefan Rehnmark، نويسنده , , Mahmoud Rahimi-Ghadim، نويسنده , , Thomas Norin، نويسنده , , Marlena Grynfarb، نويسنده , , Johnny Sandberg، نويسنده , , Gary Grover، نويسنده , , Johan Malm، نويسنده ,
Abstract :
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.
Keywords :
Thyromimetic , KB-141 , TR?-selective , binding assay , tachycardia , Thyroid stimulating hormone , ?-Amino acid , Cholesterol-fed rat model , cholesterol
