Journal of Medicinal Chemistry最新文献_第9页

Superacid-Synthesized Fluorinated Diamines Act as Selective hCA IV Inhibitors 超酸合成的氟化二胺是选择性 hCA IV 抑制剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 DOI: 10.1021/acs.jmedchem.4c01795

Emanuela Berrino, Bastien Michelet, Kassandra Vitse, Alessio Nocentini, Gianluca Bartolucci, Agnès Martin-Mingot, Paola Gratteri, Fabrizio Carta, Claudiu T. Supuran, Sébastien Thibaudeau

{"title":"Superacid-Synthesized Fluorinated Diamines Act as Selective hCA IV Inhibitors","authors":"Emanuela Berrino, Bastien Michelet, Kassandra Vitse, Alessio Nocentini, Gianluca Bartolucci, Agnès Martin-Mingot, Paola Gratteri, Fabrizio Carta, Claudiu T. Supuran, Sébastien Thibaudeau","doi":"10.1021/acs.jmedchem.4c01795","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01795","url":null,"abstract":"Carbonic anhydrase (CA) IV is a membrane-bound enzyme involved in important physio-pathological processes, such as excitation-contraction coupling in heart muscle, central nervous system (CNS) extracellular buffering, and mediation of inflammatory response after stroke. Known since the mid-1980s, this isoform is still largely unexplored when compared to other isoforms, mostly for the current lack of inhibitors targeting selectively this isoform. The discovery of selective CA IV inhibitors is thus largely awaited. In this work, we report β-(di) fluoropropyl diamines as effective CA IV inhibitors, opening real perspectives for a new mode of selective inhibition of this isoform. Inhibition data reveal that the essential structure core to ensure a potent and selective inhibition of CA IV is the N-propyldiamine. Molecular modeling studies were employed to understand the binding mode of the synthesized amines. Conformational searches within the active site space carried out in an implicit solvent (water) model were also conducted.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Potent and Selective Blockers Targeting the Epilepsy-Associated KNa1.1 Channel 发现针对癫痫相关 KNa1.1 通道的强效选择性阻断剂

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 DOI: 10.1021/acs.jmedchem.4c01815

Ruqiu Zheng, Zhongtang Li, Qiufeng Wang, Shiqi Liu, Ningfeng Liu, Yiyan Li, Guiwang Zhu, Zhenming Liu, Zhuo Huang, Liangren Zhang

{"title":"Discovery of Potent and Selective Blockers Targeting the Epilepsy-Associated KNa1.1 Channel","authors":"Ruqiu Zheng, Zhongtang Li, Qiufeng Wang, Shiqi Liu, Ningfeng Liu, Yiyan Li, Guiwang Zhu, Zhenming Liu, Zhuo Huang, Liangren Zhang","doi":"10.1021/acs.jmedchem.4c01815","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01815","url":null,"abstract":"Gain-of-function (GOF) mutations of the sodium-activated potassium channel KNa1.1 (Slack, Slo2.2, or KCa4.1) induce severe, drug-resistant forms of epilepsy in infants and children. Although quinidine has shown promise in treating KCNT1-related epilepsies compared to other drugs, its limited efficacy and substantial side effects necessitate the development of new KNa1.1 channel inhibitors. In this study, we developed a novel class of KNa1.1 inhibitors using combined silico approaches and structural optimization. Among these inhibitors, compound Z05 was identified as a selective potential KNa1.1 inhibitor, especially against the hERG channel. Moreover, its binding site and potential counteraction to a GOF mutant Y796H were identified by the mutation studies. Our data also showed that Z05 had significant pharmacological profiles, including high brain penetration and moderate oral bioavailability, offering a valuable in vitro tool compound for further drug development in treating KCNT1-related epilepsies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of Orally Active Phenylquinoline-Based Soluble Epoxide Hydrolase Inhibitors with Anti-Inflammatory and Analgesic Activity. 发现具有抗炎和镇痛活性的口服苯喹啉基可溶性环氧化物水解酶抑制剂

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 Epub Date: 2024-10-03 DOI: 10.1021/acs.jmedchem.4c01766

Jing Ding, Min-Zhen Zhu, Si-Meng Liu, Rui-Chen Liu, Shuo Xu, Kiran Shehzadi, Hong-Le Ma, Ming-Jia Yu, Xin-Hong Zhu, Jian-Hua Liang

{"title":"Discovery of Orally Active Phenylquinoline-Based Soluble Epoxide Hydrolase Inhibitors with Anti-Inflammatory and Analgesic Activity.","authors":"Jing Ding, Min-Zhen Zhu, Si-Meng Liu, Rui-Chen Liu, Shuo Xu, Kiran Shehzadi, Hong-Le Ma, Ming-Jia Yu, Xin-Hong Zhu, Jian-Hua Liang","doi":"10.1021/acs.jmedchem.4c01766","DOIUrl":"10.1021/acs.jmedchem.4c01766","url":null,"abstract":"Currently, there are no specific drugs for treating acute pancreatitis. Soluble epoxide hydrolase (sEH) inhibitors show promise, but face challenges like low blood drug concentrations and potential adverse effects on CYP enzymes and the human ether-a-go-go-related gene (hERG). In this study, an approach involving scaffold hopping and structure-activity guided optimization was employed to design a series of phenylquinoline-based sEH inhibitors. Among these compounds, DJ-53 exhibited potent in vitro and in vivo effects in alleviating pain and reducing inflammation. The in vivo mechanism of action involved inhibiting sEH enzyme activity, thereby increasing levels of anti-inflammatory epoxyeicosatrienoic acids (EETs) and decreasing levels of proinflammatory dihydroxyeicosatrienoic acids (DHETs). Importantly, DJ-53 showed exceptional oral bioavailability and pharmacokinetics, while avoiding inhibition of CYP enzymes or the hERG channel. These results highlight DJ-53's potential as a new lead compound for anti-inflammatory and analgesic applications and provide a safe and effective scaffold for developing sEH inhibitors.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

3-Deazaneplanocin A (DZNep): A Drug That Deserves a Second Look. 3-Deazaneplanocin A (DZNep)：值得重新审视的药物。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 Epub Date: 2024-10-11 DOI: 10.1021/acs.jmedchem.4c01566

Victor E Marquez

引用次数: 0

Geldanamycin, a Naturally Occurring Inhibitor of Hsp90 and a Lead Compound for Medicinal Chemistry. Geldanamycin，一种天然存在的 Hsp90 抑制剂和药物化学先导化合物。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 Epub Date: 2024-10-03 DOI: 10.1021/acs.jmedchem.4c01048

Russell R A Kitson, Dominika Kitsonová, David Siegel, David Ross, Christopher J Moody

{"title":"Geldanamycin, a Naturally Occurring Inhibitor of Hsp90 and a Lead Compound for Medicinal Chemistry.","authors":"Russell R A Kitson, Dominika Kitsonová, David Siegel, David Ross, Christopher J Moody","doi":"10.1021/acs.jmedchem.4c01048","DOIUrl":"10.1021/acs.jmedchem.4c01048","url":null,"abstract":"Geldanamycin remains a driver in the medicinal chemistry of heat shock protein 90 (Hsp90) inhibition, even half a century after its original isolation from nature. This Perspective focuses on the properties of the benzoquinone ring of the natural product that enable a range of functionalization reactions to take place. Therefore, inherent reactivity at C-17, where the methoxy group serves as a vinylogous ester, and at C-19 that demonstrates nucleophilic, enamide-type character toward electrophiles, and also as a conjugate acceptor to react with nucleophiles, has facilitated the synthesis of semisynthetic derivatives. Thus, a range of C-17-substituted amine derivatives has been investigated in oncology applications, with a number of compounds in this series reaching clinical trials. In contrast, the 19-position of geldanamycin has received less attention, although 19-substituted derivatives offer promise with markedly reduced toxicity compared to geldanamycin itself, while retaining Hsp90 inhibitory activity albeit with diminished potency in cellular studies.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Stereorandomized Oncocins with Preserved Ribosome Binding and Antibacterial Activity 具有保留核糖体结合和抗菌活性的立体随机化肿瘤球蛋白

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 DOI: 10.1021/acs.jmedchem.4c01768

Bee Ha Gan, Etienne Bonvin, Thierry Paschoud, Hippolyte Personne, Jérémie Reusser, Xingguang Cai, Robert Rauscher, Thilo Köhler, Christian van Delden, Norbert Polacek, Jean-Louis Reymond

{"title":"Stereorandomized Oncocins with Preserved Ribosome Binding and Antibacterial Activity","authors":"Bee Ha Gan, Etienne Bonvin, Thierry Paschoud, Hippolyte Personne, Jérémie Reusser, Xingguang Cai, Robert Rauscher, Thilo Köhler, Christian van Delden, Norbert Polacek, Jean-Louis Reymond","doi":"10.1021/acs.jmedchem.4c01768","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01768","url":null,"abstract":"We recently showed that solid-phase peptide synthesis using racemic amino acids yields stereorandomized peptides comprising all possible diastereomers as homogeneous, single-mass products that can be purified by HPLC and that stereorandomization modulates activity, toxicity, and stability of membrane-disruptive cyclic and linear antimicrobial peptides (AMPs) and dendrimers. Here, we tested if stereorandomization might be compatible with target binding peptides with the example of the proline-rich AMP oncocin, which inhibits the bacterial ribosome. Stereorandomization of up to nine C-terminal residues preserved ribosome binding and antibacterial effects including activities against drug-resistant bacteria and protected against serum degradation. Surprisingly, fully stereorandomized oncocin was as active as L-oncocin in dilute growth media stimulating peptide uptake, although it did not bind the ribosome, indicative of an alternative mechanism of action. These experiments show that stereorandomization can be compatible with target binding peptides and can help understand their mechanism of action.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Current Status of Computational Approaches for Small Molecule Drug Discovery 小分子药物发现计算方法的现状

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 DOI: 10.1021/acs.jmedchem.4c02462

Weijun Xu

引用次数: 0

Rethinking Medicinal Chemistry in the Cheminformatics Age. 反思化学信息时代的药物化学。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 Epub Date: 2024-10-02 DOI: 10.1021/acs.jmedchem.4c02179

Tudor I Oprea, David Weininger

引用次数: 0

Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors. 结构引导发现顺式六氢吡啶-噁嗪酮作为可逆的类药物单酰基甘油脂肪酶抑制剂。

IF 6.8 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-24 Epub Date: 2024-10-03 DOI: 10.1021/acs.jmedchem.4c01769

Bernd Kuhn, Martin Ritter, Benoit Hornsperger, Charles Bell, Buelent Kocer, Didier Rombach, Marius D R Lutz, Luca Gobbi, Martin Kuratli, Christian Bartelmus, Markus Bürkler, Raffael Koller, Paolo Tosatti, Iris Ruf, Melanie Guerard, Anto Pavlovic, Juliane Stephanus, Fionn O'Hara, Dennis Wetzl, Wiebke Saal, Martine Stihle, Doris Roth, Melanie Hug, Sylwia Huber, Dominik Heer, Carsten Kroll, Andreas Topp, Manfred Schneider, Jürg Gertsch, Sandra Glasmacher, Mario van der Stelt, Andrea Martella, Matthias Beat Wittwer, Ludovic Collin, Jörg Benz, Hans Richter, Uwe Grether

{"title":"Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors.","authors":"Bernd Kuhn, Martin Ritter, Benoit Hornsperger, Charles Bell, Buelent Kocer, Didier Rombach, Marius D R Lutz, Luca Gobbi, Martin Kuratli, Christian Bartelmus, Markus Bürkler, Raffael Koller, Paolo Tosatti, Iris Ruf, Melanie Guerard, Anto Pavlovic, Juliane Stephanus, Fionn O'Hara, Dennis Wetzl, Wiebke Saal, Martine Stihle, Doris Roth, Melanie Hug, Sylwia Huber, Dominik Heer, Carsten Kroll, Andreas Topp, Manfred Schneider, Jürg Gertsch, Sandra Glasmacher, Mario van der Stelt, Andrea Martella, Matthias Beat Wittwer, Ludovic Collin, Jörg Benz, Hans Richter, Uwe Grether","doi":"10.1021/acs.jmedchem.4c01769","DOIUrl":"10.1021/acs.jmedchem.4c01769","url":null,"abstract":"Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of the endogenous signaling ligand 2-arachidonoylglycerol, a neuroprotective endocannabinoid intimately linked to central nervous system (CNS) disorders associated with neuroinflammation. In the quest for novel MAGL inhibitors, a focused screening approach on a Roche library subset provided a reversible benzoxazinone hit exhibiting high ligand efficiency. The subsequent design of the three-dimensional cis-hexahydro-pyrido-oxazinone (cis-HHPO) moiety as benzoxazinone replacement enabled the combination of high MAGL potency with favorable ADME properties. Through enzymatic resolution an efficient synthetic route of the privileged cis-(4R,8S) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor 7o. Candidate molecule 7o matches the target compound profile of CNS drugs as it achieves high CSF exposures after systemic administration in rodents. It engages with the target in the brain and modulates neuroinflammatory processes, thus holding great promise for the treatment of CNS disorders.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cyclic Diguanylate G-Quadruplex Inducer-Quorum Sensing Inhibitor Hybrids as Bifunctional Anti-biofilm and Anti-virulence Agents Against Pseudomonas aeruginosa 作为铜绿假单胞菌双功能抗生物膜和抗微生物剂的环状二聚氰胺 G-四重链诱导剂-法定人数感应抑制剂混合物

IF 7.3 1区医学

Journal of Medicinal Chemistry Pub Date : 2024-10-23 DOI: 10.1021/acs.jmedchem.4c01253

Jie-Jiao Liu, Jing Liu, Ye-Si Huang, Wei-Min Chen, Jing Lin

{"title":"Cyclic Diguanylate G-Quadruplex Inducer-Quorum Sensing Inhibitor Hybrids as Bifunctional Anti-biofilm and Anti-virulence Agents Against Pseudomonas aeruginosa","authors":"Jie-Jiao Liu, Jing Liu, Ye-Si Huang, Wei-Min Chen, Jing Lin","doi":"10.1021/acs.jmedchem.4c01253","DOIUrl":"https://doi.org/10.1021/acs.jmedchem.4c01253","url":null,"abstract":"The release of virulence factors and biofilm formation by Pseudomonas aeruginosa are pivotal drivers of its severe pathogenicity and antibiotic resistance. Based on our prior findings, cyclic di-GMP (c-di-GMP) G-quadruplex inducers are promising biofilm inhibitors and that quorum sensing systems are central regulators of virulence, we aimed to design and synthesize c-di-GMP G-quadruplex inducer-quorum sensing inhibitor hybrids. These hybrids were envisioned as bifunctional agents with both antibiofilm and antivirulence capabilities. Hybrids A7 and A11, characterized by their quinoline and 3-indole rings, emerged as potent inhibitors. They achieve this dual action by inducing c-di-GMP G-quadruplex formation and disrupting the las and pqs signaling system. Additionally, hybrids A7 and A11 attenuated virulence factors and inhibited the motility phenotypes of P. aeruginosa. Furthermore, when tested in in vivo Caenorhabditis elegans infection models, these hybrids, in combination with antibiotics such as tetracycline, improved survival rates, all while maintaining a favorable biosafety profile.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":7.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0