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Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models 发现新型口服苯乙酰胺衍生物作为多激酶抑制剂，并在肝细胞癌动物模型中进行体内药效研究。
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-19 DOI: 10.1016/j.bmcl.2024.129971
Debasis Das, Lingzhi Xie, Dandan Qiao, Jianhe Jia, Jian Hong
{"title":"Discovery of novel, orally bioavailable phenylacetamide derivatives as multikinase inhibitors and in vivo efficacy study in hepatocellular carcinoma animal models","authors":"Debasis Das,&nbsp;Lingzhi Xie,&nbsp;Dandan Qiao,&nbsp;Jianhe Jia,&nbsp;Jian Hong","doi":"10.1016/j.bmcl.2024.129971","DOIUrl":"10.1016/j.bmcl.2024.129971","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC<sub>50</sub> values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound <strong>12</strong> and compound <strong>14</strong> were selected for <em>in vivo</em> efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129971"},"PeriodicalIF":2.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds 利用双模式 RIPK1 配体开发跨物种抗颈突变抑制化合物。
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-19 DOI: 10.1016/j.bmcl.2024.129970
József Levente Petró , Péter Bana , Nikolett Linke , Judit Eszter Szabó , Krisztina Katalin Szalai , Ildikó Kálomista , Csaba Gábor Vass , Gábor Hornyánszky , István Greiner , János Éles
{"title":"Harnessing dual-mode RIPK1 ligands for cross-species anti-necroptosis inhibitor compounds","authors":"József Levente Petró ,&nbsp;Péter Bana ,&nbsp;Nikolett Linke ,&nbsp;Judit Eszter Szabó ,&nbsp;Krisztina Katalin Szalai ,&nbsp;Ildikó Kálomista ,&nbsp;Csaba Gábor Vass ,&nbsp;Gábor Hornyánszky ,&nbsp;István Greiner ,&nbsp;János Éles","doi":"10.1016/j.bmcl.2024.129970","DOIUrl":"10.1016/j.bmcl.2024.129970","url":null,"abstract":"<div><div>Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) has a crucial role in cell death and inflammation. A promising approach to develop novel inhibitors of RIPK1 mediated necroptosis is to mix the different binding modes of the known RIPK1 inhibitors into one molecule. Herein we report the synthesis and biological evaluation of novel mixed type inhibitors. Using Eclitasertib as a starting point, and applying our previous, published knowledge regarding cyclic malonamides, we successfully identified a library of active compounds. The active enantiomer of the most balanced and promising compound was subjected to pharmacokinetics and <em>in vivo</em> hypothermia study in mice.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129970"},"PeriodicalIF":2.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
11-Azaartemisinin derivatives bearing halogenated aromatic moieties: Potent anticancer agents with high tumor selectivity 含有卤代芳香族分子的 11-青蒿素衍生物：具有高肿瘤选择性的强效抗癌剂
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-18 DOI: 10.1016/j.bmcl.2024.129969
Dung Tien Nguyen , Thuong Hanh Ngo , Mai Thanh Tran , Hao Thi Thanh Nguyen , Hien Thanh Ho , Dat Van Nguyen , Tinh Thi Nguyen , Khang Duc Ly , Thao Thi Nguyen , Tam Thi Vuong , Hung-Vu Tran
{"title":"11-Azaartemisinin derivatives bearing halogenated aromatic moieties: Potent anticancer agents with high tumor selectivity","authors":"Dung Tien Nguyen ,&nbsp;Thuong Hanh Ngo ,&nbsp;Mai Thanh Tran ,&nbsp;Hao Thi Thanh Nguyen ,&nbsp;Hien Thanh Ho ,&nbsp;Dat Van Nguyen ,&nbsp;Tinh Thi Nguyen ,&nbsp;Khang Duc Ly ,&nbsp;Thao Thi Nguyen ,&nbsp;Tam Thi Vuong ,&nbsp;Hung-Vu Tran","doi":"10.1016/j.bmcl.2024.129969","DOIUrl":"10.1016/j.bmcl.2024.129969","url":null,"abstract":"<div><p>While artemisinin and its derivatives, including 11-azaartemisinin-based compounds, have shown promising anticancer activity, the integration of halogens into aromatic structures can amplify drug potency, metabolic stability, and selectivity. Herein, we present the synthesis of new novel 11-azaartemisinin derivatives bearing halogenated aromatic moieties connected via 1,2,3‐triazole bridges and evaluate their anticancer activities against three human tumor cell lines: epidermoid carcinoma (KB), hepatocellular carcinoma (HepG2), and human lung adenocarcinoma (A549). Among the synthesized compounds, six of them (<strong>8c-h</strong>) displayed good to excellent antiproliferative activity in the low micromolar range across all three human cancer cell lines. In general, the <em>m</em>-bromide (<strong>8c</strong>) and <em>m</em>-iodide (<strong>8d</strong>) compounds exhibited superior anticancer activities compared to their <em>o</em>- and <em>p</em>-analogs, as well as the <em>m</em>-chloride and <em>m</em>-fluoride compounds. The most promising <em>m</em>-Br compound (<strong>8c</strong>) displayed 50 % inhibition of KB, HepG2, and A549 cell growth at concentrations of 7.7, 42.5, and 15.5 μM, respectively. Notably, the <em>m</em>-Br compound (<strong>8c</strong>) exhibited approximately 32-, 6-, and 16-fold lower activity in normal cells (Hek293) compared to KB, HepG2, and A549 tumor cells, respectively, indicating a significant tumor-selectivity.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129969"},"PeriodicalIF":2.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
MicroRNA-382 as a tumor suppressor during tumor progression 微RNA-382是肿瘤进展过程中的肿瘤抑制因子
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-16 DOI: 10.1016/j.bmcl.2024.129967
Yalda Samsami , Iman Akhlaghipour , Negin Taghehchian , Mahsa Palizkaran Yazdi , Saba Farrokhi , Hamid Reza Rahimi , Meysam Moghbeli
{"title":"MicroRNA-382 as a tumor suppressor during tumor progression","authors":"Yalda Samsami ,&nbsp;Iman Akhlaghipour ,&nbsp;Negin Taghehchian ,&nbsp;Mahsa Palizkaran Yazdi ,&nbsp;Saba Farrokhi ,&nbsp;Hamid Reza Rahimi ,&nbsp;Meysam Moghbeli","doi":"10.1016/j.bmcl.2024.129967","DOIUrl":"10.1016/j.bmcl.2024.129967","url":null,"abstract":"<div><p>Despite the recent progresses in therapeutic and diagnostic methods, there is still a significantly high rate of mortality among cancer patients. One of the main reasons for the high mortality rate in cancer patients is late diagnosis, which leads to the failure of therapeutic strategies. Therefore, investigation of cancer biology can lead to the introduction of early diagnostic markers in these patients. MicroRNAs (miRNAs) play an important role in regulation of cellular processes associated with tumor progression. Due to the high stability of miRNAs in body fluids, these factors can be considered as the non-invasive tumor markers. Deregulation of miR-382 has been widely reported in different cancers. Therefore, in this review, we investigated the role of miR-382 during tumor development. It has shown that miR-382 has mainly a tumor suppressive, which inhibits the growth of tumor cells through the regulation of signaling pathways, RNA-binding proteins, and transcription factors. Therefore, miR-382 can be suggested as a diagnostic and therapeutic marker in cancer patients.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129967"},"PeriodicalIF":2.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells 设计和发现具有抗三阴性乳腺癌 MDA-MB-231 细胞多方面潜力的羧酰胺基吡唑共轭物
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-16 DOI: 10.1016/j.bmcl.2024.129960
K.T Ashitha , S. Lakshmi , S. Anjali , Ajay Krishna , Ved Prakash , Sadasivam Anbumani , S. Priya , Sasidhar B. Somappa
{"title":"Design and discovery of carboxamide-based pyrazole conjugates with multifaceted potential against Triple-Negative Breast cancer MDA-MB-231 cells","authors":"K.T Ashitha ,&nbsp;S. Lakshmi ,&nbsp;S. Anjali ,&nbsp;Ajay Krishna ,&nbsp;Ved Prakash ,&nbsp;Sadasivam Anbumani ,&nbsp;S. Priya ,&nbsp;Sasidhar B. Somappa","doi":"10.1016/j.bmcl.2024.129960","DOIUrl":"10.1016/j.bmcl.2024.129960","url":null,"abstract":"<div><p>We report the design, synthesis, and validation of carboxamide-based pyrazole and isoxazole conjugates with a multifaceted activity against Breast Cancer Cell Line MDA-MB-231. The study established that amongst the series, <em>N</em>-(3,5-bis(trifluoromethyl)benzyl)-3-(3,4,5-trimethoxyphenyl)-1<em>H</em>-pyrazole-5-carboxamide (<strong>5</strong><strong>g</strong>) exhibits the highest potency in inhibiting Breast Cancer Cell Line MDA-MB-231 with an IC<sub>50</sub> value of 15.08 ± 0.04 µM. The MDA‐MB‐231 cells, upon treatment with compound <strong>5</strong><strong>g</strong>, exhibited characteristic apoptotic specific activities such as nuclear fragmentation, phosphatidylserine translocation to the outer plasma membrane, release of lactate dehydrogenase (LDH), and upregulation of caspase 3 and caspase 9 activities. Also, the modulation of pro and antiapoptotic proteins in <strong>5</strong><strong>g</strong> treated MDA-MB-231 cells was revealed by membrane array analysis. More importantly, the combination of paclitaxel and compound <strong>5</strong><strong>g</strong> has exhibited improved activity by several folds via their synergistic effects.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129960"},"PeriodicalIF":2.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Chemically induced degradation of PRC2 complex by EZH2-Targeted PROTACs via a Ubiquitin-Proteasome pathway EZH2 靶向 PROTACs 通过泛素-蛋白酶体途径对 PRC2 复合物进行化学诱导降解
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-16 DOI: 10.1016/j.bmcl.2024.129968
Mingwei Fu , Yuanjiang Wang , Min Ge , Chunchen Hu , Ya Xiao , Yan Ma , Shaohua Gou
{"title":"Chemically induced degradation of PRC2 complex by EZH2-Targeted PROTACs via a Ubiquitin-Proteasome pathway","authors":"Mingwei Fu ,&nbsp;Yuanjiang Wang ,&nbsp;Min Ge ,&nbsp;Chunchen Hu ,&nbsp;Ya Xiao ,&nbsp;Yan Ma ,&nbsp;Shaohua Gou","doi":"10.1016/j.bmcl.2024.129968","DOIUrl":"10.1016/j.bmcl.2024.129968","url":null,"abstract":"<div><p>Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that plays an important role in cancer cells biology. However, present EZH2 inhibitors in clinic have not achieved satisfactory efficacy. Herein, a number of EZH2-targeted PROTAC compounds were designed and synthesized by selecting different linkers, using Tazemetostat as the protein of interest (POI) portion of PROTAC molecules, hoping to improve the defects of existing EZH2 inhibitors effectively. Among all the target compounds, <strong>ZJ-20</strong> showed the best performance with an IC<sub>50</sub> value of 5.0 nM against MINO cells, good pharmacokinetics parameters and a limited acceptable oral bioavailability. Significantly, <strong>ZJ-20</strong> could achieve degradation of the entire PRC2 complex by targeting EZH2, which can serve as a lead compound for further study.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129968"},"PeriodicalIF":2.5,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Structure elucidation, absolute configuration, and biological evaluation of cyclic peroxides from the sponge Plakinastrella sp. 海绵 Plakinastrella sp.环过氧化物的结构阐释、绝对构型和生物学评价
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-14 DOI: 10.1016/j.bmcl.2024.129963
Rohitesh Kumar , Rhone K. Akee , Lucero Martínez-Fructuoso , Vitor F. Freire , Christopher C. Thornburg , Jason R. Evans , Brian D. Peyser , Susan Ensel , Barry R. O’Keefe , Tanja Grkovic
{"title":"Structure elucidation, absolute configuration, and biological evaluation of cyclic peroxides from the sponge Plakinastrella sp.","authors":"Rohitesh Kumar ,&nbsp;Rhone K. Akee ,&nbsp;Lucero Martínez-Fructuoso ,&nbsp;Vitor F. Freire ,&nbsp;Christopher C. Thornburg ,&nbsp;Jason R. Evans ,&nbsp;Brian D. Peyser ,&nbsp;Susan Ensel ,&nbsp;Barry R. O’Keefe ,&nbsp;Tanja Grkovic","doi":"10.1016/j.bmcl.2024.129963","DOIUrl":"10.1016/j.bmcl.2024.129963","url":null,"abstract":"<div><p>Two cyclic peroxides, plakortides V (<strong>1</strong>) and W (<strong>2</strong>) were purified from the organic extract of the sponge <em>Plakinastrella</em> sp. Their planar structures were established based on extensive NMR and MS analysis and the absolute configurations of the three stereogenic centers of the 1,2-dioxane moiety were determined to be 3<em>R</em>,4<em>S</em>,6<em>S</em> by comparative analysis of the <sup>1</sup>H NMR spectral data of the <em>R</em>- or <em>S</em>-MTPA Mosher esters<em>.</em> Compounds <strong>1</strong> and <strong>2</strong> exhibited potent cytotoxic activity against LOX IMVI (melanoma), UO-31 (renal), and HL-60 (TB) (leukemia) cell lines in the NCI-60 cytotoxicity assay.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129963"},"PeriodicalIF":2.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines 含环多胺的新型表皮生长因子受体酪氨酸激酶抑制剂的设计与活性评估
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-14 DOI: 10.1016/j.bmcl.2024.129961
Liang-Liang Guo , Yan-Hong Zhang , Jun-Fang Zuo , Yi Cheng , Guoliang Chen , Chao Li
{"title":"Design and activity evaluation of new EGFR tyrosine kinase inhibitors containing cyclic polyamines","authors":"Liang-Liang Guo ,&nbsp;Yan-Hong Zhang ,&nbsp;Jun-Fang Zuo ,&nbsp;Yi Cheng ,&nbsp;Guoliang Chen ,&nbsp;Chao Li","doi":"10.1016/j.bmcl.2024.129961","DOIUrl":"10.1016/j.bmcl.2024.129961","url":null,"abstract":"<div><p>The EGFR-TK pathway is pivotal in non-small-cell lung cancer (NSCLC) treatment, drugs targeting both EGFR wild-type and mutant tumor cells are still urgently needed. The focus of our study is on ATP-competitive inhibitors crucial for NSCLC therapy, specifically targeting the epidermal growth factor receptor (EGFR). A series of derivatives of Erlotinib and Icotinib were developed by incorporating a macrocyclic polyamine into a quinazoline scaffold to enhance their inhibitory activity against drug-resistant cells. The compounds exhibit modest activity against EGFR triple mutants (EGFR<sup>del</sup><sup>19</sup><sup>/T790M/C797S</sup>). Compound b demonstrated slightly improved inhibition activity against PC-9<sup>d</sup><sup>el19/T790M/C797S</sup> (IC<sub>50</sub> = 496.3 nM). This could provide some insights for optimizing EGFR inhibitors, particularly in the context of EGFR triple mutants.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129961"},"PeriodicalIF":2.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142242889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Identification of isoquinolinone DHODH inhibitor isosteres 鉴定异喹啉酮类 DHODH 抑制剂异构体。
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-14 DOI: 10.1016/j.bmcl.2024.129965
Lindsey G. DeRatt , Zhuming Zhang , E. Christine Pietsch , Justin Cisar , Aihua Wang , Chao-yuan Wang , Alexandra Tanner , Paul Shaffer , Edgar Jacoby , Faraz Kazmi , Neetu Shukla , Ulrike Philippar , Ricardo M. Attar , James P. Edwards , Scott D. Kuduk
{"title":"Identification of isoquinolinone DHODH inhibitor isosteres","authors":"Lindsey G. DeRatt ,&nbsp;Zhuming Zhang ,&nbsp;E. Christine Pietsch ,&nbsp;Justin Cisar ,&nbsp;Aihua Wang ,&nbsp;Chao-yuan Wang ,&nbsp;Alexandra Tanner ,&nbsp;Paul Shaffer ,&nbsp;Edgar Jacoby ,&nbsp;Faraz Kazmi ,&nbsp;Neetu Shukla ,&nbsp;Ulrike Philippar ,&nbsp;Ricardo M. Attar ,&nbsp;James P. Edwards ,&nbsp;Scott D. Kuduk","doi":"10.1016/j.bmcl.2024.129965","DOIUrl":"10.1016/j.bmcl.2024.129965","url":null,"abstract":"<div><div>DHODH inhibition represents an attractive approach to overcome differentiation blockade for the treatment of AML. In a previous communication, we described our efforts leading to the discovery of compound <strong>3</strong> (JNJ-74856665), an orally bioavailable, potent, and selective DHODH inhibitor for clinical development. Guided by the co-crystal structures bound to human DHODH, other fused six-membered constructs were explored as isosteric replacements of the isoquinolinone central core. The correct positioning of the nitrogen in these core systems proved to be essential in modulating potency. Herein is described the synthesis of these complexly functionalized cores and their profiling, leading to DHODH inhibitors that possess favorable properties suitable for further development.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129965"},"PeriodicalIF":2.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142277739","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Stability studies of β-Amino- and β-Hydroxy difluoromethyl ketones in rat serum and rat liver microsomes β-氨基和β-羟基二氟甲基酮在大鼠血清和大鼠肝脏微粒体中的稳定性研究
IF 2.5 4区 医学
Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-09-14 DOI: 10.1016/j.bmcl.2024.129964
Baharul Islam , Katherine E. Kreusel , Suresh P. Sulochana , Alex L. Nguyen , Munia F. Sowaileh , Hari R. Khatri , Madeline H. Griffin , Demetra A. Leara , David A. Colby
{"title":"Stability studies of β-Amino- and β-Hydroxy difluoromethyl ketones in rat serum and rat liver microsomes","authors":"Baharul Islam ,&nbsp;Katherine E. Kreusel ,&nbsp;Suresh P. Sulochana ,&nbsp;Alex L. Nguyen ,&nbsp;Munia F. Sowaileh ,&nbsp;Hari R. Khatri ,&nbsp;Madeline H. Griffin ,&nbsp;Demetra A. Leara ,&nbsp;David A. Colby","doi":"10.1016/j.bmcl.2024.129964","DOIUrl":"10.1016/j.bmcl.2024.129964","url":null,"abstract":"<div><p>Although difluoromethyl ketones are used as tools in chemical biology and leads in drug discovery, the metabolic stability of these compounds is generally uncharacterized and must be inferred from in vivo pharmacological assays. In order to address this gap which impedes their wider use, we have synthesized and performed metabolic stability studies for thirty-nine β-amino and β-hydroxy difluoromethyl ketones. These investigations provide structure–stability relationships of the difluoromethyl ketones following incubation with rodent serum and liver microsomes.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"113 ","pages":"Article 129964"},"PeriodicalIF":2.5,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271375","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
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