Francesco Marchesani, Francesca Rebecchi, Marco Pieroni, Serena Faggiano, Giannamaria Annunziato, Chiara Spaggiari, Stefano Bruno, Sofia Rinaldi, Roberta Giaccari, Gabriele Costantino, Barbara Campanini
{"title":"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","authors":"Francesco Marchesani, Francesca Rebecchi, Marco Pieroni, Serena Faggiano, Giannamaria Annunziato, Chiara Spaggiari, Stefano Bruno, Sofia Rinaldi, Roberta Giaccari, Gabriele Costantino, Barbara Campanini","doi":"10.1021/acsmedchemlett.4c00174","DOIUrl":null,"url":null,"abstract":"The intricate signaling network within the central nervous system (CNS) involving <i>N</i>-methyl-<span>d</span>-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 <span>d</span>-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 (<b>28</b>) has emerged as a valuable candidate with a <i>K</i><sub>d</sub> 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.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Chemical Probes to Investigate Central Nervous System Disorders: Design, Synthesis and Mechanism of Action of a Potent Human Serine Racemase Inhibitor\",\"authors\":\"Francesco Marchesani, Francesca Rebecchi, Marco Pieroni, Serena Faggiano, Giannamaria Annunziato, Chiara Spaggiari, Stefano Bruno, Sofia Rinaldi, Roberta Giaccari, Gabriele Costantino, Barbara Campanini\",\"doi\":\"10.1021/acsmedchemlett.4c00174\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The intricate signaling network within the central nervous system (CNS) involving <i>N</i>-methyl-<span>d</span>-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 <span>d</span>-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 (<b>28</b>) has emerged as a valuable candidate with a <i>K</i><sub>d</sub> 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.\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-07-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1021/acsmedchemlett.4c00174\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acsmedchemlett.4c00174","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Chemical Probes to Investigate Central Nervous System Disorders: Design, Synthesis and Mechanism of Action of a Potent Human Serine Racemase Inhibitor
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 Kd 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.
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.