Research article2007Peer reviewed
Thyroid receptor ligands. Part 8: Thyromimetics derived from N-acylated-alpha-amino acid derivatives displaying modulated pharmacological selectivity compared with KB-141
Garg, Neeraj; Li, Yi-Lin; Collazo, Ana Maria Garcia; Litten, Chris; Ryono, Denis E.; Zhang, Minsheng; Caringal, Yolanda; Brigance, Robert P.; Meng, Wei; Washburn, William N.; Agback, Peter; Mellstrom, Karin; Rehnmark, Stefan; Rahimi-Ghadim, Mahmoud; Norin, Thomas; Grynfarb, Marlena; Sandberg, Johnny; Grover, Gary; Malm, Johan
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 TR beta(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. (c) 2007 Elsevier Ltd. All rights reserved.
Keywords
KB-141; thyromimetic; alpha-amino acid; binding assay; TR beta-selective; cholesterol-fed rat model; cholesterol; thyroid stimulating hormone; tachycardia
Published in
Bioorganic and Medicinal Chemistry Letters
2007, Volume: 17, number: 15, pages: 4131-4134 Publisher: PERGAMON-ELSEVIER SCIENCE LTD
UKÄ Subject classification
Organic Chemistry
Publication identifier
DOI: https://doi.org/10.1016/j.bmcl.2007.05.049
Permanent link to this page (URI)
https://res.slu.se/id/publ/83873