RESUMEN
A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats.
Asunto(s)
Fenilpropionatos/síntesis química , Piridinas/síntesis química , Receptores de Hormona Tiroidea/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Ligandos , Modelos Moleculares , Fenilpropionatos/química , Fenilpropionatos/farmacología , Piridinas/química , Piridinas/farmacología , Ratas , Receptores alfa de Hormona Tiroidea/antagonistas & inhibidores , Receptores beta de Hormona Tiroidea/antagonistas & inhibidores , Receptores beta de Hormona Tiroidea/química , Activación Transcripcional/efectos de los fármacosRESUMEN
Based on the examination of the X-ray crystallographic structures of the LBD of TRalpha and TRbeta in complex with KB-141 (2), a number of novel 4'-hydroxy bioisosteric thyromimetics were prepared. Optimal affinity and beta-selectivity (33 times), was found with a medium-sized alkyl-substituted amido group; iso-butyl (12c). It can be concluded that bioisosteric replacements of the 4'-hydroxy position represent a new promising class of TRbeta-selective synthetic thyromimetics.
Asunto(s)
Amidas/farmacología , Receptores beta de Hormona Tiroidea/efectos de los fármacos , Amidas/síntesis química , Amidas/química , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Éteres Fenílicos/química , Fenilacetatos/química , Conformación Proteica , Estructura Terciaria de Proteína , Relación Estructura-Actividad , Receptores alfa de Hormona Tiroidea/efectos de los fármacos , Hormonas Tiroideas/química , Triyodotironina/químicaRESUMEN
Based on the recently described concept of "indirect antagonism" of nuclear receptors, a series of thyroid hormone receptor (TR) antagonists were prepared, in which the outer ring of a thyromimetic was replaced with alkyl chains of variable length and branch. The results of a binding assay for the human TR and reporter cell assay revealed, within this series, a positive correlation between increasing bulk of the alkyl group and affinity to TRs. Compared with already reported TR antagonists, their affinities are within the same range, thus potentially representing a useful approach to novel and high affinity TR-antagonists.