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

Affiliation

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.

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