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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Design, synthesis and biological evaluation of novel TR beta selective agonists sustained by ADME-toxicity analysis
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Design, synthesis and biological evaluation of novel TR beta selective agonists sustained by ADME-toxicity analysis

机译：通过Adme毒性分析维持的新型TRβ选择性激动剂的设计，合成和生物学评价

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Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the alpha isoform of thyroid hormone receptors (Tits) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the beta isoform that could induce some beneficial effects (i.e. lowering triglyceride and cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRB and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as "potentially safe" to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TR beta-selective thyromimetics. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：虽然三碘甲酚（T3）诱导脂质代谢的几种有益效果，但其使用受到毒性副作用的阻碍，例如心动过速，心律失常，心力衰竭，骨骼和肌肉分解代谢和情绪干扰。由于甲状腺激素受体（奶）的α亚型是T3相关的有害影响的主要原因，已经作出了一些努力来开发测试亚型选择性激动剂可能引起一些有利的影响（即降低甘油三酯和胆固醇水平减少肥胖并改善代谢综合征），同时克服了大多数不利的T3依赖性副作用。在此，我们描述了通过Adme毒性分析持续的药物发现过程，导致我们鉴定具有同种型TRB的选择性的新型激动剂和可接受的脱靶和吸收，分布代谢，排泄和毒性（Adme-Tox）型材。在一系列中，在合成的一系列化合物中，衍生物1和3，从该分析中出现，作为从事临床前研究的“潜在安全”。在体外调查中证明，两种化合物都能够减少HepG2中的脂质积累，并促进与T3引发的相当效果的脂解，用作参考药物。此外，体内研究的初步证实了表观缺乏毒性，因此表明化合物1和3作为新的潜在TRβ选择性晶体Ismetics。 （c）2019年Elsevier Masson SAS。版权所有。

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