Chemical Probes to Investigate Central Nervous System Disorders: Design, Synthesis and Mechanism of Action of a Potent Human Serine Racemase Inhibitor

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-07-03 DOI:10.1021/acsmedchemlett.4c00174

Francesco Marchesani, Francesca Rebecchi, Marco Pieroni, Serena Faggiano, Giannamaria Annunziato, Chiara Spaggiari, Stefano Bruno, Sofia Rinaldi, Roberta Giaccari, Gabriele Costantino, Barbara Campanini

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Abstract

The intricate signaling network within the central nervous system (CNS) involving N-methyl-d-aspartate receptors (NMDARs) has been recognized as a key player in severe neurodegenerative diseases. The indirect modulation of NMDAR-mediated neurotransmission through inhibition of serine racemase (SR)─the enzyme responsible for the synthesis of the NMDAR coagonist d-serine─has been suggested as a therapeutic strategy to treat these conditions. Despite the inherent challenges posed by SR conformational flexibility, a ligand-based drug design strategy has successfully produced a series of potent covalent inhibitors structurally related to amino acid analogues. Among these inhibitors, O-(2-([1,1′-biphenyl]-4-yl)-1-carboxyethyl)hydroxylammonium chloride (28) has emerged as a valuable candidate with a K_d of about 5 μM, which makes it one of the most potent hSR inhibitors reported to date. This molecule is expected to inspire the identification of selective hSR inhibitors that might find applications as tools in the study and treatment of several CNS pathologies.

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研究中枢神经系统疾病的化学探针：一种强效人丝氨酸消旋酶抑制剂的设计、合成及其作用机制

中枢神经系统（CNS）内涉及 N-甲基-d-天冬氨酸受体（NMDAR）的信号网络错综复杂，已被认为是严重神经退行性疾病的关键因素。通过抑制丝氨酸外消旋酶（SR）--一种负责合成 NMDAR 拮抗剂 d-丝氨酸的酶--来间接调节 NMDAR 介导的神经传递，已被认为是治疗这些疾病的一种治疗策略。尽管SR的构象灵活性带来了固有的挑战，但基于配体的药物设计策略已成功研制出一系列在结构上与氨基酸类似物相关的强效共价抑制剂。在这些抑制剂中，O-(2-([1,1′-联苯]-4-基)-1-羧乙基)羟基氯化铵(28)已成为一种有价值的候选化合物，其 Kd 约为 5 μM，是迄今为止报道的最有效的 hSR 抑制剂之一。该分子有望激发选择性 hSR 抑制剂的鉴定，这些抑制剂可能会被用作研究和治疗多种中枢神经系统疾病的工具。

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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.