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

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Garg N, Li YL, Garcia Collazo AM, Litten C, Ryono DE, Zhang M, Caringal Y, Brigance RP, Meng W, Washburn WN, Agback P, Mellstrom K, Rehnmark S, Rahimi-Ghadim M, Norin T, Grynfarb M, Sandberg J, Grover G, Malm J

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. Epub 2007 May 21.

PubMed ID
17543524 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
KB-141Thyroid hormone receptor alphaIC 50 (nM)2574Details
KB-141Thyroid hormone receptor alphaEC 50 (nM)1.774Details
KB-141Thyroid hormone receptor betaIC 50 (nM)1.174Details
KB-141Thyroid hormone receptor betaEC 50 (nM)0.7874Details
LiothyronineThyroid hormone receptor alphaIC 50 (nM)0.2474Details
LiothyronineThyroid hormone receptor betaIC 50 (nM)0.2674Details