Structure-Based Optimization of Selective and Brain Penetrant CK1δ Inhibitors for the Treatment of Circadian Disruptions

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-03-07 DOI:10.1021/acsmedchemlett.3c00523

Stefan McCarver*, Luke Hanna, Andrew Samant, Aaron A. Thompson, Mark Seierstad, Arjun Saha, Dongpei Wu, Brian Lord, Steven W. Sutton, Vishal Shah, Cynthia M. Milligan, Michelle Wennerholm, Jonathan Shelton, Terry P. Lebold and Brock T. Shireman,

引用次数: 0

Abstract

Neuropsychiatric disorders such as major depressive disorders and schizophrenia are often associated with disruptions to the normal 24 h sleep wake cycle. Casein kinase 1 (CK1δ) is an integral part of the molecular machinery that regulates circadian rhythms. Starting from a cluster of bicyclic pyrazoles identified from a virtual screening effort, we utilized structure-based drug design to identify and reinforce a unique “hinge-flip” binding mode that provides a high degree of selectivity for CK1δ versus the kinome. Pharmacokinetics, brain exposure, and target engagement as measured by ex vivo autoradiography are described for advanced analogs.

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基于结构优化治疗昼夜节律紊乱的选择性和脑穿透性 CK1δ 抑制剂

重度抑郁症和精神分裂症等神经精神疾病通常与正常的 24 小时睡眠觉醒周期被打乱有关。酪蛋白激酶 1（CK1δ）是调节昼夜节律的分子机制中不可或缺的一部分。从虚拟筛选工作中发现的一组双环吡唑开始，我们利用基于结构的药物设计来确定和加强一种独特的 "铰链-翻转 "结合模式，这种模式为 CK1δ 与激酶组提供了高度的选择性。我们介绍了高级类似物的药代动力学、脑暴露以及通过体内外自显影测量的目标参与情况。

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

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.