{"title":"Novel Indole Derivatives as Serotonergic Psychedelic Agents for Treating Psychosis, Mental Illness, and CNS Disorders","authors":"Ram W. Sabnis*, ","doi":"10.1021/acsmedchemlett.5c0030910.1021/acsmedchemlett.5c00309","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00309https://doi.org/10.1021/acsmedchemlett.5c00309","url":null,"abstract":"<p >Provided herein are novel indole derivatives as serotonergic psychedelic agents, pharmaceutical compositions, use of such compounds in treating psychosis, mental illness and central nervous system (CNS) disorders, and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"982–983 982–983"},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144260992","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 Application of Novel Arginine Vasopressin Receptor 1A (AVPR1A) Antagonists.","authors":"Xin Zhou, Steven H Liang","doi":"10.1021/acsmedchemlett.5c00285","DOIUrl":"10.1021/acsmedchemlett.5c00285","url":null,"abstract":"<p><p>Arginine Vasopressin Receptor 1A (AVPR1A) is a member of G-protein-coupled receptors (GPCRs) that binds arginine vasopressin (AVP) and is primarily related to cardiovascular function, glycogenolysis, and social behaviors. This patent describes the synthesis of a series of AVPR1A antagonists and their applications in related disease treatment.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"963-964"},"PeriodicalIF":3.5,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169450/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315549","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":"Deuterated 1,3 Dihydro‑2<i>H</i>‑indole-2-one Derivatives for Treatment of Depression or Anxiety.","authors":"Qi-Long Hu, Steven H Liang","doi":"10.1021/acsmedchemlett.5c00284","DOIUrl":"10.1021/acsmedchemlett.5c00284","url":null,"abstract":"<p><p>This patent application discloses a series of l,3-dihydro-2<i>H</i>-indol-2-one derivatives targeting the vasopressin 1b receptor (V<sub>1b</sub>) or both the V<sub>1a</sub> and V<sub>1b</sub> receptors, as represented by Formula I. These vasopressin receptor antagonists exhibit significant therapeutic potential, particularly for the treatment of depression or anxiety, and hold promises for benefiting patients with reduced dosing frequency.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"965-966"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315513","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":"Novel Tetrahydrocyclohepteneindole Derivatives Targeting Estrogen Receptor Alpha for the Treatment of Breast Cancer.","authors":"Zhendong Song, Steven H Liang","doi":"10.1021/acsmedchemlett.5c00283","DOIUrl":"10.1021/acsmedchemlett.5c00283","url":null,"abstract":"<p><p>This patent presents novel substituted tetrahydrocyclohepteneindole derivatives as selective estrogen receptor alpha (ERα) inhibitors. These compounds demonstrate potential for treating Erα-related diseases such as cancers, ovulatory dysfunction, endometriosis, and inflammation diseases.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"967-969"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315539","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":"Discovery of Indole-Based PDE5 Inhibitors: Synthesis and Pharmacological Evaluation.","authors":"Shin-Young Park, Dang Pham, Param Shukla, Justin Edward, Reshmi John, Addison Li, Michael Hadjiargyrou, Mattia Mori, Elisa Zuccarello, Ottavio Arancio, Jole Fiorito","doi":"10.1021/acsmedchemlett.5c00108","DOIUrl":"10.1021/acsmedchemlett.5c00108","url":null,"abstract":"<p><p>Phosphodiesterase 5 (PDE5) inhibitors have been suggested as new treatments for Alzheimer's disease (AD) and other conditions such as cancer and cardiovascular diseases. Utilizing the widespread presence of the indole moiety in biomolecules and drugs, previously synthesized quinoline and naphthyridine compounds were modified into novel indole-containing PDE5 inhibitors. Replacing the amine with an amide group led to identifying a potent analogue, compound <b>14a</b>, with an IC<sub>50</sub> of 16.11 nM. Molecular docking simulations further highlight the significance of the amide group in drug-target interactions. A cytotoxicity test and a parallel artificial membrane permeability assay validated the compound's potential as a lead for further drug development. Compound <b>14a</b> was shown to be safe and blood-brain barrier permeable. The discovery of these indole-containing PDE5 inhibitors provides new perspectives for developing PDE5 therapeutics.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1058-1065"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315518","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":"Deuterated 1,3 Dihydro-2H-indole-2-one Derivatives for Treatment of Depression or Anxiety","authors":"Qi-Long Hu, and , Steven H. Liang*, ","doi":"10.1021/acsmedchemlett.5c0028410.1021/acsmedchemlett.5c00284","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00284https://doi.org/10.1021/acsmedchemlett.5c00284","url":null,"abstract":"<p >This patent application discloses a series of l,3-dihydro-2<i>H</i>-indol-2-one derivatives targeting the vasopressin 1b receptor (V<sub>1b</sub>) or both the V<sub>1a</sub> and V<sub>1b</sub> receptors, as represented by Formula I. These vasopressin receptor antagonists exhibit significant therapeutic potential, particularly for the treatment of depression or anxiety, and hold promises for benefiting patients with reduced dosing frequency.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"965–966 965–966"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261205","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 Tetrahydrocyclohepteneindole Derivatives Targeting Estrogen Receptor Alpha for the Treatment of Breast Cancer","authors":"Zhendong Song, and , Steven H. Liang*, ","doi":"10.1021/acsmedchemlett.5c0028310.1021/acsmedchemlett.5c00283","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00283https://doi.org/10.1021/acsmedchemlett.5c00283","url":null,"abstract":"<p >This patent presents novel substituted tetrahydrocyclohepteneindole derivatives as selective estrogen receptor alpha (ERα) inhibitors. These compounds demonstrate potential for treating Erα-related diseases such as cancers, ovulatory dysfunction, endometriosis, and inflammation diseases.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"967–969 967–969"},"PeriodicalIF":3.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261224","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}
Shin-Young Park, Dang Pham, Param Shukla, Justin Edward, Reshmi John, Addison Li, Michael Hadjiargyrou, Mattia Mori, Elisa Zuccarello, Ottavio Arancio and Jole Fiorito*,
{"title":"Discovery of Indole-Based PDE5 Inhibitors: Synthesis and Pharmacological Evaluation","authors":"Shin-Young Park, Dang Pham, Param Shukla, Justin Edward, Reshmi John, Addison Li, Michael Hadjiargyrou, Mattia Mori, Elisa Zuccarello, Ottavio Arancio and Jole Fiorito*, ","doi":"10.1021/acsmedchemlett.5c0010810.1021/acsmedchemlett.5c00108","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00108https://doi.org/10.1021/acsmedchemlett.5c00108","url":null,"abstract":"<p >Phosphodiesterase 5 (PDE5) inhibitors have been suggested as new treatments for Alzheimer’s disease (AD) and other conditions such as cancer and cardiovascular diseases. Utilizing the widespread presence of the indole moiety in biomolecules and drugs, previously synthesized quinoline and naphthyridine compounds were modified into novel indole-containing PDE5 inhibitors. Replacing the amine with an amide group led to identifying a potent analogue, compound <b>14a</b>, with an IC<sub>50</sub> of 16.11 nM. Molecular docking simulations further highlight the significance of the amide group in drug-target interactions. A cytotoxicity test and a parallel artificial membrane permeability assay validated the compound’s potential as a lead for further drug development. Compound <b>14a</b> was shown to be safe and blood-brain barrier permeable. The discovery of these indole-containing PDE5 inhibitors provides new perspectives for developing PDE5 therapeutics.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1058–1065 1058–1065"},"PeriodicalIF":3.5,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.5c00108","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261221","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}
Jennifer M VanNatta, Graham J Carlson, Haichan Niu, Ruoli Bai, Hashini I Wanniarachchi, Regan Schuetze, Mary Lynn Trawick, Ernest Hamel, Ralph P Mason, Kevin G Pinney
{"title":"Benzosuberene and Tetracyclic Analogues as Colchicine Site Inhibitors of Tubulin Polymerization.","authors":"Jennifer M VanNatta, Graham J Carlson, Haichan Niu, Ruoli Bai, Hashini I Wanniarachchi, Regan Schuetze, Mary Lynn Trawick, Ernest Hamel, Ralph P Mason, Kevin G Pinney","doi":"10.1021/acsmedchemlett.5c00129","DOIUrl":"10.1021/acsmedchemlett.5c00129","url":null,"abstract":"<p><p>Colchicine site inhibitors of tubulin polymerization function as antiproliferative anticancer agents, with certain inhibitors demonstrating a dual mechanism of action as tumor-selective vascular disrupting agents (VDAs). Our previous studies yielded potent benzosuberene-based colchicine site inhibitors of tubulin polymerization. To expand structure-activity correlations, the seven-membered fused ring and the pendant ring were modified to generate a series of new compounds, 11 being strong inhibitors (IC<sub>50</sub> ≤ 5 μM) of tubulin polymerization. Structural modifications introduced a second benzylic olefin and, separately, a nitrogen atom to the fused seven-membered ring, along with conversion to unique tetracyclic fused ring systems. Two of the active inhibitors were synthetically converted to corresponding phosphate prodrug salts to increase aqueous solubility for <i>in vivo</i> studies. In a preliminary study of VDA efficacy, these prodrugs caused blood flow disruption in mice, as revealed by bioluminescence imaging with histological confirmation. The most effective analogues from this series offer promise as cancer therapeutic agents.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1098-1107"},"PeriodicalIF":3.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315510","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}
Jennifer M. VanNatta, Graham J. Carlson, Haichan Niu, Ruoli Bai, Hashini I. Wanniarachchi, Regan Schuetze, Mary Lynn Trawick, Ernest Hamel, Ralph P. Mason and Kevin G. Pinney*,
{"title":"Benzosuberene and Tetracyclic Analogues as Colchicine Site Inhibitors of Tubulin Polymerization","authors":"Jennifer M. VanNatta, Graham J. Carlson, Haichan Niu, Ruoli Bai, Hashini I. Wanniarachchi, Regan Schuetze, Mary Lynn Trawick, Ernest Hamel, Ralph P. Mason and Kevin G. Pinney*, ","doi":"10.1021/acsmedchemlett.5c0012910.1021/acsmedchemlett.5c00129","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00129https://doi.org/10.1021/acsmedchemlett.5c00129","url":null,"abstract":"<p >Colchicine site inhibitors of tubulin polymerization function as antiproliferative anticancer agents, with certain inhibitors demonstrating a dual mechanism of action as tumor-selective vascular disrupting agents (VDAs). Our previous studies yielded potent benzosuberene-based colchicine site inhibitors of tubulin polymerization. To expand structure–activity correlations, the seven-membered fused ring and the pendant ring were modified to generate a series of new compounds, 11 being strong inhibitors (IC<sub>50</sub> ≤ 5 μM) of tubulin polymerization. Structural modifications introduced a second benzylic olefin and, separately, a nitrogen atom to the fused seven-membered ring, along with conversion to unique tetracyclic fused ring systems. Two of the active inhibitors were synthetically converted to corresponding phosphate prodrug salts to increase aqueous solubility for <i>in vivo</i> studies. In a preliminary study of VDA efficacy, these prodrugs caused blood flow disruption in mice, as revealed by bioluminescence imaging with histological confirmation. The most effective analogues from this series offer promise as cancer therapeutic agents.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 6","pages":"1098–1107 1098–1107"},"PeriodicalIF":3.5,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261132","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}