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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome
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Privileged scaffold-based design to identify a novel drug-like 5-HT7 receptor-preferring agonist to target Fragile X syndrome

机译：基于脚手架的特权设计，以鉴定一种新的药物样5-HT7受体 - 偏美激动剂，以靶向脆弱的X综合征

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Recent preclinical studies have shown that activation of the serotonin 5-HT7 receptor has the potential to treat neurodevelopmental disorders such as Fragile X syndrome, a rare disease characterized by autistic features. With the aim to provide the scientific community with diversified drug-like 5-HT7 receptor-preferring agonists, we designed a set of new long-chain arylpiperazines by exploiting structural fragments present in clinically approved drugs or in preclinical candidates (privileged scaffolds). The new compounds were synthesized, tested for their affinity at 5-HT7 and 5-HT1A receptors, and screened for their in vitro stability to microsomal degradation and toxicity. Selected compounds were characterized as 5-HT7 receptor-preferring ligands, endowed with high metabolic stability and low toxicity. Compound 7g emerged as a drug-like 5-HT7 receptor-preferring agonist capable to rescue synaptic plasticity and attenuate stereotyped behavior in a mouse model of Fragile X syndrome. (C) 2020 Published by Elsevier Masson SAS.
机译：最近的临床前研究表明，血清素5-HT7受体的激活具有治疗神经发育障碍，例如易碎X综合征，其特征是自闭症特征的罕见疾病。旨在为科学界提供多样化的药物样5-HT7受体偏好激动剂，我们通过临床批准的药物或临床前候选人（特权支架）来设计一组新的长链芳基哌嗪。合成新化合物，在5-HT7和5-HT1A受体中测试其亲和力，并筛选它们对微粒体降解和毒性的体外稳定性。所选择的化合物的特征为5-HT7受体偏好配体，赋予高代谢稳定性和低毒性。化合物7G作为一种药物样5-HT7受体偏好激动剂，能够拯救突触塑性度并衰减脆弱X综合征小鼠模型中的刻板作用。 （c）2020由Elsevier Masson SA发表。

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