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Predictions of Chromatography Methods by Chemical Structure Similarity to Accelerate High-Throughput Medicinal Chemistry 通过化学结构相似性预测色谱方法,加快高通量药物化学的发展
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-12 DOI: 10.1021/acsmedchemlett.4c00145
Jun Wang, Rose Yen, Armen G. Beck, Pankaj Aggarwal, May Kong, Michael Hayes, Salman Jabri, Thomas J. Greshock, Kanaka Hettiarachchi
We introduce a new workflow that relies heavily on chemical quantitative structure-retention relationship (QSRR) models to accelerate method development for micro/mini-scale high-throughput purification (HTP). This provides faster access to new active pharmaceutical ingredients (APIs) through high-throughput experimentation (HTE). By comparing fingerprint structural similarity (e.g., Tanimoto index) with small training data sets containing a few hundred diverse small molecule antagonists of a lipid metabolizing enzyme, we can predict retention time (RT) of new compounds. Machine learning (ML) helps to identify optimal separation conditions for purification without performing the traditional crude QC step involving ultrahigh performance liquid chromatography (UHPLC) analyses of each compound. This green-chemistry approach with the use of predictive tools reduces cost and significantly shortens the design-make-test (DMT) cycle of new drugs by way of HTE.
我们介绍了一种新的工作流程,它主要依靠化学定量结构-保留关系(QSRR)模型来加速微/小规模高通量纯化(HTP)的方法开发。这样就能通过高通量实验 (HTE) 更快地获得新的活性药物成分 (API)。通过比较指纹结构相似性(如谷本指数)与包含几百种不同小分子脂质代谢酶拮抗剂的小型训练数据集,我们可以预测新化合物的保留时间(RT)。机器学习(ML)有助于确定纯化的最佳分离条件,而无需执行传统的粗质量控制步骤,即对每个化合物进行超高效液相色谱(UHPLC)分析。这种使用预测工具的绿色化学方法通过 HTE 降低了成本,并大大缩短了新药的设计-制造-测试 (DMT) 周期。
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引用次数: 0
Novel Glucagon-like Peptide 1 Receptor Agonists for Treating Type II Diabetes 治疗 II 型糖尿病的新型胰高血糖素样肽 1 受体激动剂
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-11 DOI: 10.1021/acsmedchemlett.4c00303
Ram W. Sabnis
Provided herein are novel glucagon-like peptide-1 receptor agonists, pharmaceutical compositions, use of such compounds in treating type II diabetes, and processes for preparing such compounds.
本文提供了新型胰高血糖素样肽-1 受体激动剂、药物组合物、此类化合物在治疗 II 型糖尿病中的用途以及制备此类化合物的工艺。
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引用次数: 0
In This Issue, Volume 15, Issue 7 本期,第 15 卷第 7 期
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-11 DOI: 10.1021/acsmedchemlett.4c00282
Andrew P. Riley*, 
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引用次数: 0
Novel Compounds as NLRP3 Inhibitors for Treating Cardiovascular Diseases 作为 NLRP3 抑制剂治疗心血管疾病的新型化合物
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-11 DOI: 10.1021/acsmedchemlett.4c00304
Ram W. Sabnis
Provided herein are novel compounds as NLRP3 inhibitors, pharmaceutical compositions, use of such compounds in treating cardiovascular diseases, and processes for preparing such compounds.
本文提供了作为 NLRP3 抑制剂的新型化合物、药物组合物、此类化合物在治疗心血管疾病中的用途以及制备此类化合物的工艺。
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引用次数: 0
Systematical Mutational Analysis of FRATtide against Osteoclast Differentiation by Alanine Scanning 通过丙氨酸扫描对抗击破骨细胞分化的 FRATtide 基因进行系统突变分析
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-10 DOI: 10.1021/acsmedchemlett.4c00127
Yi Yang, Chenchen Geng, Huaxing Shen, Jingru Chao, Zhe Wang, Wei Cong, Xiang Li, Guangming Ye, Yunyun Jiang
Osteoporosis, a global bone disease, results in decreased bone density, mass, and microarchitecture deterioration, increasing fracture risk. In previous research, FRATtide, a peptide derived from a glycogen synthase kinase-3 binding protein, effectively hindered osteoclast differentiation to yield therapeutically potent derivatives via single and double stapling. However, FRATtide’s structure–activity relationship remains unclear. This study synthesized 25 FRATtide-derived peptides through systematic alanine scanning and evaluated their activities. Substitutions in Pro2, Leu5, Leu9, Val10, Leu11, Ser12, Asn14, Leu15, Ile16, Glu18, Arg22, Ser25, and Arg26 showed reduced activity, while FRT13 and FRT20 with Gly13 and Arg21 substitutions, respectively, displayed enhanced activities. F-actin binding and bone resorption assays on FRT13 and FRT20 showed better inhibition of osteoclast differentiation and bone resorption compared with FRATtide. This study elucidated FRATtide’s structure–activity relationship, thereby facilitating future structural optimization for osteoporosis treatment.
骨质疏松症是一种全球性骨病,会导致骨密度、骨量减少和微结构退化,增加骨折风险。在以前的研究中,FRATtide 是一种从糖原合酶激酶-3 结合蛋白中提取的多肽,它能有效阻碍破骨细胞的分化,通过单钉和双钉产生具有治疗效果的衍生物。然而,FRATtide 的结构-活性关系仍不清楚。本研究通过系统的丙氨酸扫描合成了 25 种 FRATtide 衍生肽,并评估了它们的活性。Pro2、Leu5、Leu9、Val10、Leu11、Ser12、Asn14、Leu15、Ile16、Glu18、Arg22、Ser25 和 Arg26 的取代显示出活性降低,而分别取代 Gly13 和 Arg21 的 FRT13 和 FRT20 则显示出活性增强。与 FRATtide 相比,FRT13 和 FRT20 的 F-肌动蛋白结合和骨吸收试验表明,它们能更好地抑制破骨细胞分化和骨吸收。这项研究阐明了 FRATtide 的结构-活性关系,从而促进了未来骨质疏松症治疗的结构优化。
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引用次数: 0
Discovery of Broad-Spectrum Herpes Antiviral Oxazolidinone Amide Derivatives and Their Structure–Activity Relationships 发现广谱抗疱疹病毒的噁唑烷酮酰胺衍生物及其结构-活性关系
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-09 DOI: 10.1021/acsmedchemlett.4c00117
Michael A. Plotkin, Marc Labroli, Jeffrey Schubert, Anthony Shaw, Kelly-Ann S. Schlegel, Richard Berger, Andrew J. Cooke, Robert P. Hayes, Kira A. Armacost, Keith Kinek, Paula Krosky, Christine Burlein, Shi Meng, Edward DiNunzio, Edward M. Murray, Sony Agrawal, Maria Madeira, Amy Flattery, Huifang Yao, Andrew Leithead, William A Rose, II, Christopher Cox, David M. Tellers, Philip M. McKenna, Izzat Raheem
Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity. Herpesviruses share a conserved DNA polymerase, the inhibition of which is validated as an effective strategy to disrupt viral replication. By utilizing a non-nucleoside inhibitor of the viral DNA polymerase, we sought to develop agents covering multiple herpesviruses (e.g., CMV, VZV, HSV1/2, EBV, and HHV6). Herein is described the invention of an oxazolidinone class of broad-spectrum non-nucleoside herpes antiviral inhibitors. A lead compound (42) with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV infection.
疱疹病毒感染无处不在,95% 以上的成年人至少感染过一种病毒。对于健康人来说,这些感染大多无需治疗即可缓解,但对于免疫力低下、干细胞或器官移植患者来说,它们会导致严重的发病率和死亡率。目前的核苷类药物治疗标准虽能提供有意义的益处,但由于耐受性差、耐药性和活性谱普遍较窄而受到限制。疱疹病毒共享一种保守的DNA聚合酶,抑制这种酶已被证实是破坏病毒复制的有效策略。通过利用病毒 DNA 聚合酶的非核苷抑制剂,我们试图开发出涵盖多种疱疹病毒(如 CMV、VZV、HSV1/2、EBV 和 HHV6)的制剂。本文介绍了一种噁唑烷酮类广谱非核苷疱疹抗病毒抑制剂的发明。在小鼠模型中发现,一种先导化合物(42)具有强大的生化活性和广谱细胞活性,对 HSV-1 和 CMV 感染均有疗效。
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引用次数: 0
Novel Imidazopyridine and Imidazopyridazine Derivatives as DGAT2 Inhibitors for Treating Multiple Diseases 作为 DGAT2 抑制剂治疗多种疾病的新型咪唑并哒嗪和咪唑并哒嗪衍生物
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-03 DOI: 10.1021/acsmedchemlett.4c00286
Ram W. Sabnis
Provided herein are novel imidazopyridine and imidazopyridazine derivatives as DGAT2 inhibitors, pharmaceutical compositions, use of such compounds in treating multiple diseases, and processes for preparing such compounds.
本文提供了作为 DGAT2 抑制剂的新型咪唑并哒嗪和咪唑并哒嗪衍生物、药物组合物、此类化合物在治疗多种疾病中的用途以及制备此类化合物的工艺。
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引用次数: 0
AI Based Discovery of a New AKR1C3 Inhibitor for Anticancer Applications 基于人工智能发现新型 AKR1C3 抗癌抑制剂
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-03 DOI: 10.1021/acsmedchemlett.4c00150
Agnese C. Pippione, Chiara Vigato, Cristina Tucciarello, Samrina Hussain, Edoardo Salladini, Ha H. Truong, Niel M. Henriksen, Gaia Vanzetti, Giorgia Giordano, Daniele Zonari, Osman Asghar Mirza, Karla Frydenvang, Ymera Pignochino, Simonetta Oliaro-Bosso, Donatella Boschi, Marco L. Lolli
AKR1C3 is an upregulated enzyme in prostate and other cancers; in addition to regulating hormone synthesis, this enzyme is thought to play a role in the aggressiveness of tumors and in the defense against drugs. We here used an unbiased method to discover new potent AKR1C3 inhibitors: through an AI-based virtual drug screen, compound 4 was identified as a potent and selective enzymatic inhibitor able to translate this activity into a pronounced antiproliferative effect in the 22RV1 prostate cancer cell model. As other known AKR1C3 inhibitors, compound 4 determined a significantly increased activity of abiraterone, a drug approved for advanced prostate cancer. Compound 4 also showed a synergic effect with doxorubicin in osteosarcoma cell lines; specifically, the effect is correlated with AKR1C3 expression. In this research work, therefore, the use of AI allowed the identification of a new structure as an AKR1C3 inhibitor and its potential to enhance the effect of chemotherapeutics.
AKR1C3 是前列腺癌和其他癌症中的一种上调酶;除了调节激素合成外,这种酶还被认为在肿瘤的侵袭性和抵御药物方面发挥作用。在这里,我们采用了一种无偏见的方法来发现新的强效 AKR1C3 抑制剂:通过基于人工智能的虚拟药物筛选,化合物 4 被鉴定为一种强效的选择性酶抑制剂,能够在 22RV1 前列腺癌细胞模型中将这种活性转化为明显的抗增殖作用。与其他已知的 AKR1C3 抑制剂一样,化合物 4 能显著提高阿比特龙的活性,阿比特龙是一种已被批准用于晚期前列腺癌的药物。化合物 4 还在骨肉瘤细胞系中显示出与多柔比星的协同作用;特别是,这种作用与 AKR1C3 的表达相关。因此,在这项研究工作中,通过使用人工合成技术,确定了一种新结构的 AKR1C3 抑制剂,并发现了其增强化疗效果的潜力。
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引用次数: 0
Chemical Probes to Investigate Central Nervous System Disorders: Design, Synthesis and Mechanism of Action of a Potent Human Serine Racemase Inhibitor 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
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL 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
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.
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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引用次数: 0
Correction to “Novel Antiproliferative Chimeric Compounds with Marked Histone Deacetylase Inhibitory Activity” 对 "具有明显组蛋白去乙酰化酶抑制活性的新型抗增殖嵌合化合物 "的更正
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-07-03 DOI: 10.1021/acsmedchemlett.4c00301
Elisa Giacomini, Angela Nebbioso, Alfonso Ciotta, Cristina Ianni, Federico Falchi, Marinella Roberti, Manlio Tolomeo, Stefania Grimaudo, Antonietta Di Cristina, Rosaria Maria Pipitone, Lucia Altucci, Maurizio Recanatini
Page 976. An error was found in the originally published version of Figure 3. The corrected figure is shown here. Figure 3. Western blot analyses carried out for the indicated targets in U937 and MCF-7 cells after 24 h of treatment. ImageJ was used to quantify protein expression. Histone H1, H4 and ERKs indicate equal loading. SAHA and trans-6 were used at concentration of 5 μM. This article has not yet been cited by other publications. Figure 3. Western blot analyses carried out for the indicated targets in U937 and MCF-7 cells after 24 h of treatment. ImageJ was used to quantify protein expression. Histone H1, H4 and ERKs indicate equal loading. SAHA and trans-6 were used at concentration of 5 μM.
第 976 页。在最初出版的图 3 中发现了一处错误。现将更正后的图示于此。图 3.对处理 24 小时后的 U937 和 MCF-7 细胞中的指定靶标进行的 Western 印迹分析。使用 ImageJ 对蛋白质表达进行量化。组蛋白 H1、H4 和 ERKs 表示等量加载。SAHA 和反式-6 的浓度为 5 μM。本文尚未被其他出版物引用。图 3.处理 24 小时后,对 U937 和 MCF-7 细胞中的指定靶标进行的 Western 印迹分析。使用 ImageJ 对蛋白质表达进行量化。组蛋白 H1、H4 和 ERKs 表示等量加载。SAHA 和反式-6 的浓度为 5 μM。
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引用次数: 0
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ACS Medicinal Chemistry Letters
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