从高通量筛选中鉴定出强效、选择性和外周受限的 5-羟色胺受体 2B 拮抗剂。
Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen.
机构信息
Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Franklin, Tennessee, USA.
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
出版信息
Assay Drug Dev Technol. 2023 Apr;21(3):89-96. doi: 10.1089/adt.2022.116. Epub 2023 Mar 17.
Abstract
Antagonists of the serotonin receptor 2B (5-HT) have shown great promise as therapeutics for the treatment of pulmonary arterial hypertension, valvular heart disease, and related cardiopathies. Herein, we describe a high-throughput screen campaign that led to the identification of highly potent and selective 5-HT antagonists. Furthermore, selected compounds were profiled for their predicted ability to cross the blood-brain barrier. Two exemplary compounds, VU0530244 and VU0631019, were predicted to have very limited potential for brain penetration in human subjects, a critical profile for the development of 5-HT antagonists devoid of centrally-mediated adverse effects.
摘要
5-羟色胺受体 2B（5-HT）拮抗剂在肺动脉高压、心脏瓣膜病和相关心脏疾病的治疗方面显示出巨大的潜力。在此，我们描述了一项高通量筛选活动，该活动导致发现了高活性和选择性的 5-HT 拮抗剂。此外，还对选定的化合物进行了预测其穿透血脑屏障能力的研究。两种典型的化合物，VU0530244 和 VU0631019，被预测在人体中具有非常有限的穿透大脑的潜力，这对于开发没有中枢介导的不良反应的 5-HT 拮抗剂来说是一个关键的特征。
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