a Houston Methodist Research Institute, Genomic Medicine Program , 6565 Fannin Street, Fondren 8-060, Houston , TX 77030 , USA.
b Technological University of Monterrey, ITESM, Monterrey , Mexico.
Expert Opin Ther Targets. 2016;20(2):145-9. doi: 10.1517/14728222.2016.1090429. Epub 2015 Nov 13.
Sobetirome binds selectively to the main hepatic form of thyroid hormone (TH) receptor, TRβ1, compared to TRα1, which is principally responsible for thyrotoxic effects on heart, muscle and bone. Sobetirome also preferentially accumulates in liver. It was originally envisaged that sobetirome could be used to stimulate hepatic pathways that lower cholesterol without harmful side effects and might be used in conjunction with statins. Indeed, sobetirome progressed through preclinical animal studies and Phase I human clinical trials with excellent results and without obvious harmful side effects. Despite the fact that cardiovascular disease remains a major cause of mortality and that new therapies are desperately needed, it is unlikely that sobetirome will progress in further human clinical trials in the near future. The emergence of alternative cholesterol-lowering therapeutics may render selective thyromimetics redundant. Further, fears of thyrotoxic effects in the heart and emergence of cartilage defects in dogs after long-term use of eprotirome, a similar though not identical compound, has reduced enthusiasm for this strategy. We argue that it is nevertheless important to explore uses of sobetirome in humans; more treatment strategies would help patients with hard-to-treat dyslipidemias. Sobetirome may also have additional applications in orphan indications and short-term controlled weight loss.
索贝替欧与甲状腺激素（TH）受体的主要肝型 TRβ1 选择性结合，而 TRα1 主要负责甲状腺素对心脏、肌肉和骨骼的毒性作用。索贝替欧也优先在肝脏中积累。最初设想，索贝替欧可以用于刺激肝脏途径，降低胆固醇，而不会产生有害的副作用，并且可能与他汀类药物联合使用。事实上，索贝替欧在临床前动物研究和 I 期人体临床试验中取得了很好的结果，没有明显的有害副作用。尽管心血管疾病仍然是主要的死亡原因，并且急需新的治疗方法，但在不久的将来，索贝替欧不太可能在进一步的人体临床试验中取得进展。替代降胆固醇治疗方法的出现可能会使选择性甲状腺刺激剂变得多余。此外，由于长期使用类似但不完全相同的化合物依罗替欧后，狗出现了心脏毒性和软骨缺陷的担忧，人们对这种策略的热情降低了。我们认为，在人类中探索索贝替欧的用途仍然很重要；更多的治疗策略将有助于治疗难以治疗的血脂异常患者。索贝替欧在孤儿病适应证和短期控制体重减轻方面也可能有额外的应用。
