甲状腺受体配体。1。beta1甲状腺受体激动剂配体选择性。

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你们L,李YL Mellstrom K,梅林C, Bladh LG、克勒K,加戈N,加西亚Collazo,闪亮的C, Husman B。佩尔松K, Ljunggren J,格罗弗·G, Sleph PG,乔治•R白垩土J

甲状腺受体配体。1。beta1甲状腺受体激动剂配体选择性。

J地中海化学。2003年4月24日,46 (9):1580 - 8。

PubMed ID

12699376 (在PubMed

]

文摘

内生甲状腺激素受体3、5、3 ',5 ' -tetraiodo-l-thyronine (T (4), 1), 3, 5, 3 ' -triiodo-l-thyronine (T(3), 2)对经济增长起到重要作用,开发,并在哺乳动物体内平衡。他们调节肠道内的重要基因,骨骼和心脏肌肉、肝脏、中枢神经系统,影响整体的代谢率,胆固醇和甘油三酯的水平,和心率,影响情绪和整体的感觉。文献表明许多或者大多数甲状腺激素对心脏的影响,尤其是心率和节律,通过TRalpha介导(1)同种型,虽然大多数行为的荷尔蒙对肝脏和其他组织通过TRbeta介导多(1)同种型受体。一些甲状腺激素的影响可能是治疗有用nonthyroid障碍如果可以最小化或消除不利影响。这些潜在的有用特性包括减肥治疗肥胖,降低胆固醇治疗高脂血症,改善抑郁,刺激骨形成的骨质疏松症。之前试图利用甲状腺激素药物治疗这些疾病一直受限于甲状腺机能亢进的表现,特别是心血管毒性。因此,开发的甲状腺激素受体受体激动剂选择性beta-isoform可能导致安全治疗这些常见疾病,同时避免毒性。我们在这里描述的合成和评价的一系列小说TR配体,它们为TRbeta选择性(1)TRalpha (1)。这些配体可能是有用的治疗各种疾病如前所述。从一系列同源R(1)取代羧酸衍生物,链长增加被发现的亲和力和选择性产生深远影响的放射性受体结合分析人类甲状腺激素受体α(1)和β(1)(TRalpha(1)和TRbeta(2)),以及一个记者细胞测定采用CHOK1-cells(中国仓鼠卵巢细胞)的稳定性与hTRalpha(1)或hTRbeta(1)和碱性磷酸酶报告基因下游甲状腺响应元件(TRAFalpha(1)和TRAFbeta (1))。 Affinity increases in the order formic, acetic, and propionic acid, while beta-selectivity is highest when the R(1) position is substituted with acetic acid. Within this series 3,5-dibromo-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (11a) and 3,5-dichloro-4-[(4-hydroxy-3-isopropylphenoxy)phenyl]acetic acid (15) were found to reveal the most promising in vitro data based on isoform selectivity and were selected for further in vivo studies. The effect of 2, 11a, and 15 in a cholesterol-fed rat model was monitored including potencies for heart rate (ED(15)), cholesterol (ED(50)), and TSH (ED(50)). Potency for tachycardia was significantly reduced for the TRbeta selective compounds 11a and 15 compared with 2, while both 11a and 15 retained the cholesterol-lowering potency of 2. This left an approximately 10-fold therapeutic window between heart rate and cholesterol, which is consistent with the action of ligands that are approximately 10-fold more selective for TRbeta(1). We also report the X-ray crystallographic structures of the ligand binding domains of TRalpha and TRbeta in complex with 15. These structures reveal that the single amino acid difference in the ligand binding pocket (Ser277 in TRalpha or Asn331 in TRbeta) results in a slightly different hydrogen bonding pattern that may explain the increased beta-selectivity of 15.

DrugBank数据引用了这篇文章

多肽

的名字	UniProt ID
甲状腺激素受体β	P10828	细节
甲状腺激素受体α	P10827	细节

绑定属性

药物	目标	财产	测量	pH值	温度(°C)
kb - 141	甲状腺激素受体α	集成电路50 (nM)	25	7	4	细节
kb - 141	甲状腺激素受体α	EC 50 (nM)	11	7	4	细节
kb - 141	甲状腺激素受体β	集成电路50 (nM)	1.1	7	4	细节
kb - 141	甲状腺激素受体β	EC 50 (nM)	3.5	7	4	细节
碘塞罗宁	甲状腺激素受体α	集成电路50 (nM)	0.24	7	4	细节
碘塞罗宁	甲状腺激素受体β	集成电路50 (nM)	0.26	7	4	细节
Tiratricol	甲状腺激素受体β	集成电路50 (nM)	0.048	7	4	细节