Bioorganic & Medicinal Chemistry最新文献

{"title":"Discovery of IDOR-1117-1680, a dual orexin receptor antagonist with fast onset and short duration of action for the treatment of insomnia","authors":"Jean-Philippe Surivet,&nbsp;Elise M. Jacob,&nbsp;Melanie Kessler,&nbsp;Christopher Kohl,&nbsp;Catherine Vaillant,&nbsp;Olivier Bezençon,&nbsp;Patrick Bouis,&nbsp;Louise Busch,&nbsp;Jean-Christophe Gauvin,&nbsp;Manon Kiry,&nbsp;Chara Litou,&nbsp;Florence Masse,&nbsp;Cary-Ann Mathieu,&nbsp;Azely Mirre,&nbsp;Jens-Uwe Peters,&nbsp;Timo Rager,&nbsp;Markus Rey,&nbsp;Raphaël Ruetsch,&nbsp;Michel Alexander Steiner","doi":"10.1016/j.bmc.2025.118132","DOIUrl":"10.1016/j.bmc.2025.118132","url":null,"abstract":"<div><div>We describe the optimization of 2-acyl-1-biarylmethylpyrazolidines, a novel class of dual orexin receptor antagonists (DORAs) designed for the treatment of sleep disorders requiring a rapid onset (&lt;30<!--> <!--> min) and a short duration of action (2–4 h). Building on the previously identified lead compound DORA <strong>4</strong>, our optimization program yielded several potent pyrazolidine DORAs with carefully tailored <em>in vitro</em> physicochemical and DMPK (drug, metabolism and pharmacokinetics) properties. <em>In vivo</em> studies in animals, combined with pharmacokinetic-pharmacodynamic (PK-PD) simulations, demonstrated that DORA <strong>31</strong> and DORA (<em>R</em>)-<strong>38</strong> effectively induced sleep in dogs and met the <em>in silico</em> predicted requirements for rapid onset and short duration in humans. Further analysis of their covalent binding potential in human hepatocytes prioritized DORA <strong>31</strong> as the preferred molecule for additional safety and biopharmaceutical evaluation. In this report we summarize and present the results of all studies that supported the selection of DORA <strong>31</strong> (IDOR-1117-1680) as a preclinical development candidate.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118132"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel cationic dihydropyrrol-2-one compounds as antimicrobial agents and quorum sensing inhibitors","authors":"Dittu Suresh ,&nbsp;Tsz Tin Yu ,&nbsp;Rajesh Kuppusamy ,&nbsp;Shekh Sabir ,&nbsp;Theerthankar Das ,&nbsp;David StC Black ,&nbsp;Mark D.P. Willcox ,&nbsp;Naresh Kumar","doi":"10.1016/j.bmc.2025.118137","DOIUrl":"10.1016/j.bmc.2025.118137","url":null,"abstract":"<div><div>Antimicrobial resistance has grown to become a global crisis consistently participating in the death of millions worldwide and accumulating costs on healthcare. Quorum sensing inhibition is a new alternative antimicrobial strategy that has been gaining attention due to its ability to suppress the resistance of <em>Pseudomonas aeruginosa</em> (PA). This approach shows great potential in overcoming bacterial resistance and could provide a much needed substitute to conventional antibiotics in the future. PA has 3 main quorum sensing systems of which the <em>Las</em> system has been identified to be the most viable therapeutic target. In this study, we report the synthesis of a library of novel broad-spectrum quorum sensing inhibitors from the dihydropyrrol-2-one scaffold to form urea and imidazolium analogues. Molecular docking was performed in parallel to synthesis to aid design. It also confirmed that the molecules comfortably occupy the ligand binding domain in addition to potential key interactions commonly present in <em>LasR</em> inhibitors. As predicted, these compounds displayed low bactericidal effects against <em>P. aeruginosa</em> with most compounds exhibiting MIC of &gt;250 μM, while maintaining moderate activity towards <em>Escherichia coli</em> with the most potent compound having an MIC of 32 μM. The greatest bactericidal effects were present on <em>Staphylococcus aureus</em> with the thiourea based molecule <strong>10c</strong> showed the highest antibacterial activity with MIC of 16 µM. Furthermore, several molecules displayed highly potent quorum sensing inhibitory activity with compounds <strong>10g</strong> and <strong>9e</strong> both demonstrating over 70 % inhibition respectively of the <em>LasR</em> system at 16 µM. These compounds also expressed inhibition of pyocyanin within <em>P. aeruginosa</em> and haemolytic assay indicates a low level of cell lysis and hence low toxicity of the compounds, further demonstrating the potential of these novel compounds.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118137"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143579837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis and activity evaluation of 4-(quinoline-2-yl)aniline derivatives as SARS-CoV‑2 main protease inhibitors","authors":"Honglei Bao ,&nbsp;Hui Meng ,&nbsp;Shilin Gong ,&nbsp;Yaguo Gong ,&nbsp;Gao Tu ,&nbsp;Zhenya Du ,&nbsp;Yuwei Wang ,&nbsp;Jianlin Wu ,&nbsp;Chunhua Ma ,&nbsp;Qinhai Ma ,&nbsp;Xiaojun Yao","doi":"10.1016/j.bmc.2025.118135","DOIUrl":"10.1016/j.bmc.2025.118135","url":null,"abstract":"<div><div>Since 2020, numerous compounds have been investigated for their potential use in treating SARS-CoV-2 infections. By identifying the molecular targets during the virus replication process, rationally designed anti-SARS-CoV-2 agents are developed. Among these targets, the main protease (M^pro) is a crucial enzyme required for virus replication, and its highly conserved characteristic make it an important drug target for the development of anti-SARS-CoV-2 drugs. Herein, we utilized warhead-based design strategy to conduct the structural optimization of <strong>M-1</strong> developed through virtual screening, leading to a series of novel M^pro inhibitors with 4-(quinolin-2-yl)aniline scaffold. Among them, <strong>M-32</strong> exhibited good SARS-CoV-2 M^pro inhibitory activity (IC₅₀ = 5.2 μM) with a nearly 25-fold increase. Isothermal titration calorimetry (ITC) directly proved that <strong>M-32</strong> binds directly to SARS-CoV-2 M^pro in an entropy-driven manner. Mass spectrometry (MS) further confirmed the covalent binding ability of <strong>M-32</strong> to M^pro. Meanwhile, <strong>M-32</strong> effectively inhibited the replication of SARS-CoV-2 in Vero E6 cells (EC₅₀ = 5.29 μM).</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118135"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in chemically inducible modified tRNA sequencing techniques: Elucidating novel insights into tRNA epitranscriptomics","authors":"Xuan Li ,&nbsp;Linqian Mu ,&nbsp;Jiaying Liu ,&nbsp;Kaidi Pengyang,&nbsp;Siqi Qin,&nbsp;Mingxing Zhou,&nbsp;Xiaoqian Chen,&nbsp;Yuyang Guo,&nbsp;Rui Wang","doi":"10.1016/j.bmc.2025.118138","DOIUrl":"10.1016/j.bmc.2025.118138","url":null,"abstract":"<div><div>In this review, we examine and expound upon the most recent and groundbreaking advancements in the sequencing of tRNA modifications, focusing specifically on the innovative chemical treatment approaches that have revolutionized this field. By delving into the intricate details of these cutting-edge methodologies, we aim to provide an overview of the current state of the art in tRNA modification sequencing, highlighting their unique strengths, limitations, and potential applications.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118138"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143529479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of fixed phosphorus position on activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors","authors":"Md. Ayub Ali ,&nbsp;Mona A. Maalouf ,&nbsp;Dan Feng ,&nbsp;Mamunur Rashid ,&nbsp;Nathaniel R. Gehrke ,&nbsp;Yashpal S. Chhonker ,&nbsp;Daryl J. Murry ,&nbsp;David F. Wiemer ,&nbsp;Sarah A. Holstein","doi":"10.1016/j.bmc.2025.118140","DOIUrl":"10.1016/j.bmc.2025.118140","url":null,"abstract":"<div><div>Geranylgeranyl diphosphate synthase (GGDPS) produces the 20-carbon isoprenoid species used in protein geranylgeranylation reactions. Inhibition of GGDPS has emerged as a novel means of disrupting the activity of geranylgeranylated proteins in cancers such as myeloma and osteosarcoma. We have focused on developing a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, demonstrating a complex structure–activity relationship (SAR), not only at the enzymatic level, but also at the cellular and whole organism levels. To further investigate this SAR, we have prepared a family of novel derivatives that have a fixed phosphorus position by virtue of vinyl, epoxy or cyclopropyl groups that incorporate the α-carbon position. Additional modifications include compounds with homocitronellyl chains instead of homogeranyl or homoneryl chains. All new compounds were evaluated in GGDPS enzyme assays and in cellular assays involving a panel of human myeloma and osteosarcoma cell lines. The homocitronellyl derivatives displayed markedly reduced activity in both enzymatic and cellular assays. While all of the homogeranyl/homoneryl vinyl/epoxy/cyclopropyl compounds had relatively similar activity in the enzyme assay (IC₅₀’s 0.37–2.87 μM), the cellular potencies varied more dramatically (ranging from 10 nM to no activity at 100 μM), depending on the olefin stereochemistry, the specific α-carbon modification and the tumor cell type. These findings, coupled with POM-prodrug and membrane permeability studies, support the hypothesis that there are specific membrane transporters mediating cellular uptake of these GGDPS inhibitors. Future studies focused on the identification of the membrane transporters responsible for the cellular uptake will enable further understanding of this complex SAR.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118140"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and evaluation of fluorinated tetrahydrocarbazoles as probes in NMR based binding assay of the E. coli β sliding clamp","authors":"Cecilie Elisabeth Olsen ,&nbsp;Signe Simonsen ,&nbsp;Srinivas Reddy Merugu ,&nbsp;Vaclav Eigner ,&nbsp;Finn L. Aachmann ,&nbsp;Birthe B. Kragelund ,&nbsp;Eirik Sundby ,&nbsp;Bård Helge Hoff","doi":"10.1016/j.bmc.2025.118139","DOIUrl":"10.1016/j.bmc.2025.118139","url":null,"abstract":"<div><div>Bacterial β sliding clamp (β-clamp) is an emerging drug target currently lacking small-molecule inhibitors with good <em>in vivo</em> activity. Thus, there is a need for fast and simple screening methods for identifying inhibitor candidates. Here we demonstrate the use of nuclear magnetic resonance spectroscopy (NMR) for evaluating compound binding to the <em>E. coli</em> β-clamp. To identify suitable molecular probes, a series of tetrahydrocarbazoles were synthesized, some of which contain fluorine. Key challenges in the synthesis were formation of regioisomers during the Fischer indole reaction and reducing racemization at the stereogenic center. The tetrahydrocarbazoles were assayed against the <em>E. coli</em> β-clamp by saturation-transfer difference (STD) NMR, waterLOGSY and <em>T</em>_1ρ. Analysis by isothermal titration calorimetry gave <em>K</em>_D-values of 1.7–14 μM for three fluorinated probe candidates, and NMR chemical shift perturbation experiments confirmed these molecules to directly interact with the β-clamp binding pocket. Binding of the fluorinated molecules to β-clamp was easily observed with ¹⁹F-observed <em>T</em>₂-based binding experiments, and proof of concept for a fluorine-based binding assay for <em>E. coli</em> β-clamp binders is provided.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118139"},"PeriodicalIF":3.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated computational and biosensor-based strategies for the discovery of allosteric SMYD3 ligands using diperodon as a starting point","authors":"Edward A. FitzGerald ,&nbsp;Moira M. Rachman ,&nbsp;Daniela Cederfelt ,&nbsp;Nadine E.M. Myers ,&nbsp;Daria Kovryzchenko ,&nbsp;He Zhang ,&nbsp;Xavier Barril ,&nbsp;Konrad Koehler ,&nbsp;U. Helena Danielson","doi":"10.1016/j.bmc.2025.118134","DOIUrl":"10.1016/j.bmc.2025.118134","url":null,"abstract":"<div><div>SMYD3 (SET- and MYND-domain containing protein 3) is an epigenetic enzyme with lysine methyl transferase activity and multiple protein binding partners. It is implicated in cancer development and active site inhibitors with antitumor activity have been developed. We have previously discovered that diperodon is an allosteric SMYD3 ligand and are interested in developing ligands that can interfere with non-catalytic functions of SMYD3, while avoiding conceivable draw-backs of targeting a conserved site in an enzyme with several close family members. Herein, the features of the diperodon site were explored via computational modelling and served as a basis for identifying analogues in commercial compound space, thus avoiding the need for in-house compound synthesis. Time-resolved grating coupled interferometry (GCI) biosensor analysis confirmed that two out of 21 acquired analogues interacted with SMYD3, with similar affinities as diperodon (<em>K</em>_D ∼ 180 and 210 <em>vs.</em> ∼200 µM). As a second approach, fragmentation of diperodon followed by growing of fragments identified an additional 11 compounds in commercial compound space. GCI analysis confirmed that <em>N</em>-phenylformamide and three compounds evolved from this fragment interacted with SMYD3. These four ligands varied structurally from diperodon and had higher affinities (<em>K</em>_D = 0.4–130 µM) and superior ligand efficiencies. However, all ligands interacted with rapid kinetics and weak affinities, indicating that the site had poor ligandability, possibly a result of its extremely flexible structure. Difficulties in protein production and the overall flexible structure of SMYD3, prevented NMR experiments and X-ray crystallography. Nevertheless, the combination of computational ligand design supported by biosensor-based analyses resulted in new allosteric ligands with minimal resources in a short time.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118134"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Designing novel nucleoside inhibitors targeting the allosteric site of PBP2a: A strategic approach to overcome resistance in MRSA","authors":"Shuting Yao ,&nbsp;Chao Fang ,&nbsp;Binjie Xu ,&nbsp;Yue Hu ,&nbsp;Zhou Chen ,&nbsp;Xiaoyan Xue ,&nbsp;Jiping Liu ,&nbsp;Mingkai Li ,&nbsp;Pengyu Li","doi":"10.1016/j.bmc.2025.118133","DOIUrl":"10.1016/j.bmc.2025.118133","url":null,"abstract":"<div><div>Due to the prolonged misuse of antimicrobial agents and the development of various resistance mechanisms, Methicillin-resistant <em>Staphylococcus aureus</em> (MRSA) has emerged as a leading threat to the public health. The production of a penicillin binding protein 2a (PBP2a) plays a crucial role in cell wall synthesis of MRSA, and conformational alterations in PBP2a impede the effective binding of β-lactam antibiotics, the most effective class of antibiotic, to the active site. The PBP2a allosteric site located 60 Å from the active site, and binding of allosteric site significantly influences the conformational dynamics of the active site. Based on the effect of nucleoside which re-sensitizes MRSA to β-lactam antibiotics, we conducted extensive virtual screening to design and synthesize a series of novel nucleoside inhibitors targeting the allosteric site of MRSA PBP2a. These inhibitors exhibit a distinct chemical structure compared to existing clinical antibiotics. Notably, compound <strong>13e</strong> demonstrated a minimum inhibitory concentration (MIC) of 16 µg/mL against MRSA strain, showcasing superior antibacterial activity relative to the reference antibiotic. Time-kill curve indicated that compound <strong>13e</strong> effectively inhibit bacterial growth. Interestingly, a synergistic effect was observed at low concentrations of compound <strong>13e</strong> in combination treatment with Oxacillin, whereas antagonism occurred at higher concentrations of compound <strong>13e</strong>. The morphological observation showed the integrity of the bacterial cell wall was disrupted after compound <strong>13e</strong> treatment, and it exhibited a lower propensity for developing resistance compared to cephalosporin. Additionally, this compound did not affect the viability of normal human intestinal epithelial cells (HIEC) and brain microvascular endothelial cells at concentration much higher than MIC. Over all, this unique antibacterial mechanism underscores the optimization potential of these nucleoside compounds, providing new perspectives and methodologies for the development of novel antimicrobial agents.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"122 ","pages":"Article 118133"},"PeriodicalIF":3.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143535166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-HBV activity of (R)-gentiandiol, a metabolite of Swertiamarin, in transgenic mice: Insights from non-targeted serum metabolomics","authors":"Yidan Sun ,&nbsp;Shuhan Tang ,&nbsp;Yaqi Xu ,&nbsp;Hao Li ,&nbsp;Pengyu Li ,&nbsp;Masao Hattori ,&nbsp;Hailong Zhang ,&nbsp;Xianna Li ,&nbsp;Zhigang Wang","doi":"10.1016/j.bmc.2025.118128","DOIUrl":"10.1016/j.bmc.2025.118128","url":null,"abstract":"<div><div>Swertiamarin, a predominant component in many traditional Chinese swertia herbs, shows significant anti-HBV activity clinically. (<em>R</em>)-gentiandiol and (<em>S</em>)-gentiandiol are the metabolites of swertiamarin <em>in vivo</em>. In this study, HBsAg, HBeAg and HBV-DNA were determined in liver tissue of HBV-transgenic C57BL/6NCrl mice to analyze anti-HBV activities of swertiamarin, (<em>R</em>)-gentiandiol and (<em>S</em>)-gentiandiol. It was found that HBsAg, HBeAg and HBV-DNA levels were significantly reduced in a dose-dependent manner when (<em>R</em>)-gentiandiol was administered at 1.5, 3 and 6 mg/kg. However, (<em>S</em>)-gentiandiol showed no anti-HBV activity at all. In addition, we also performed untargeted metabolomics to discover biomarkers and metabolic pathways of swertiamarin and (<em>R</em>)-gentiandiol in HBV-transgenic C57BL/6NCrl mice. A total of 15 candidate biomarkers were obtained. Meanwhile, the metabolic disorders including 8 metabolic pathways, such as taurine and hypotaurine metabolism were explored. Taurine and hypotaurine metabolism was the primary pathway for (<em>R</em>)-gentiandiol to regulate HBV-transgenic C57BL/6NCrl mice. It is the first time to clarify real active anti-HBV metabolites of swertiamarin, which can offer more insights into anti-HBV activities of swertia herbs, and bring novel ideas for new drug development in anti-HBV herbs.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118128"},"PeriodicalIF":3.3,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biosynthesis and structure assignment of a hydroxylated metabolite of the orexin-1 receptor antagonist JNJ-61393215","authors":"Fengbin Song ,&nbsp;Jie Chen ,&nbsp;Shannon Dallas ,&nbsp;Wing Lam ,&nbsp;Heng-Keang Lim ,&nbsp;Ronghui Zhou ,&nbsp;Tetsuo Kokubun ,&nbsp;Richard Phipps ,&nbsp;Jonathan Steele ,&nbsp;Rhys Salter","doi":"10.1016/j.bmc.2025.118130","DOIUrl":"10.1016/j.bmc.2025.118130","url":null,"abstract":"<div><div>JNJ-61393215, a deuterated compound, is a selective OX1R antagonist. In both preclinical and clinical studies, a hydroxylated metabolite designated M54 was observed to be the most abundant metabolite in plasma. Screening of Hypha PolyCYPs®⁺ kit revealed PolyCYP 152 was the most proficient at producing M54 from JNJ-61393215 and subsequent scale up with PolyCYP 152 provided small but sufficient quantities of M54 for initial structure elucidation by NMR analyses. A microbial biosynthesis, using a Streptomyces strain from which PolyCYP 152 was genetically derived, provided gram quantities of M54. It allowed chemical epimerization of the chiral hydroxylated carbon of M54 and unequivocally established the metabolite’s absolute stereo-configuration. The biotransformation provided remarkably efficient methodologies for quick synthesis of the metabolite M54 with stereoselective hydroxylation on the deuterated unique 2-aza-[2.2.1]-bicycle core structure, for which structure assignment via classical synthesis of speculative structures would be challenging and resource-intensive. Moreover, the microbial biosynthesis provided M54 with high purity for ongoing preclinical studies.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"121 ","pages":"Article 118130"},"PeriodicalIF":3.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143520616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}