Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen.

IF 1.6 4区医学 Q4 BIOCHEMICAL RESEARCH METHODS

Assay and drug development technologies Pub Date : 2023-04-01 Epub Date: 2023-03-17 DOI:10.1089/adt.2022.116

Aaron M Bender, Michael S Valentine, Joshua A Bauer, Emily Days, Craig W Lindsley, W David Merryman

引用次数: 0

Abstract

Antagonists of the serotonin receptor 2B (5-HT_2B) 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_2B 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_2B antagonists devoid of centrally-mediated adverse effects.

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通过高通量筛选鉴定强效、选择性和外周限制性羟色胺受体 2B 拮抗剂

5-羟色胺受体 2B（5-HT2B）拮抗剂作为治疗肺动脉高压、瓣膜性心脏病和相关心脏病的药物已显示出巨大的前景。在本文中，我们介绍了一项高通量筛选活动，通过该活动发现了高效力和高选择性的 5-HT2B 拮抗剂。此外，我们还分析了所选化合物穿越血脑屏障的预测能力。根据预测，VU0530244 和 VU0631019 这两种典型化合物在人体中的脑穿透潜力非常有限，而这正是开发无中枢介导不良反应的 5-HT2B 拮抗剂的关键所在。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Assay and drug development technologies 医学-生化研究方法

CiteScore

3.60

自引率

0.00%

发文量

审稿时长

>12 weeks

期刊介绍： ASSAY and Drug Development Technologies provides access to novel techniques and robust tools that enable critical advances in early-stage screening. This research published in the Journal leads to important therapeutics and platforms for drug discovery and development. This reputable peer-reviewed journal features original papers application-oriented technology reviews, topical issues on novel and burgeoning areas of research, and reports in methodology and technology application. ASSAY and Drug Development Technologies coverage includes: -Assay design, target development, and high-throughput technologies- Hit to Lead optimization and medicinal chemistry through preclinical candidate selection- Lab automation, sample management, bioinformatics, data mining, virtual screening, and data analysis- Approaches to assays configured for gene families, inherited, and infectious diseases- Assays and strategies for adapting model organisms to drug discovery- The use of stem cells as models of disease- Translation of phenotypic outputs to target identification- Exploration and mechanistic studies of the technical basis for assay and screening artifacts