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

  • Bioorg Med Chem Lett. 2007 Aug 1;17(15):4131-4. doi: 10.1016/j.bmcl.2007.05.049.
Neeraj Garg  1 ,  Yi-Lin Li ,  Ana Maria Garcia Collazo ,  Chris Litten ,  Denis E Ryono ,  Minsheng Zhang ,  Yolanda Caringal ,  Robert P Brigance ,  Wei Meng ,  William N Washburn ,  Peter Agback ,  Karin Mellström ,  Stefan Rehnmark ,  Mahmoud Rahimi-Ghadim ,  Thomas Norin ,  Marlena Grynfarb ,  Johnny Sandberg ,  Gary Grover ,  Johan Malm
Affiliations
  • 1. Karo Bio AB, Novum, Huddinge S-141 57, Sweden.
PMID: 17543524 DOI: 10.1016/j.bmcl.2007.05.049
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-alpha-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 TRbeta(1)-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.