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ACS Medicinal Chemistry Letters最新文献

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IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-10
Ram W. Sabnis*, 
{"title":"","authors":"Ram W. Sabnis*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"XXX-XXX 12260–12268"},"PeriodicalIF":3.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00321","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587222","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}
引用次数: 0
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-10
Mark P. Farrell, 
{"title":"","authors":"Mark P. Farrell, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"XXX-XXX 12260–12268"},"PeriodicalIF":3.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00388","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587229","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}
引用次数: 0
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-10
{"title":"","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"XXX-XXX 12260–12268"},"PeriodicalIF":3.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/mlv016i007_1957036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587237","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}
引用次数: 0
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-10
Rushan Fei, Na Lin, Xin Zhang, Lei Xu, Qingnan Zhang, Zhichao Pan, Xiaowu Dong* and Weilin Wang*, 
{"title":"","authors":"Rushan Fei, Na Lin, Xin Zhang, Lei Xu, Qingnan Zhang, Zhichao Pan, Xiaowu Dong* and Weilin Wang*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"XXX-XXX 12260–12268"},"PeriodicalIF":3.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00173","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587245","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}
引用次数: 0
IF 3.5 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-10
Ryan A. Bragg*, Jonas Bergare, Markus Artelsmair, William J. Kerr, Troels Skrydstrup and Charles S. Elmore*, 
{"title":"","authors":"Ryan A. Bragg*, Jonas Bergare, Markus Artelsmair, William J. Kerr, Troels Skrydstrup and Charles S. Elmore*, ","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 7","pages":"XXX-XXX 12260–12268"},"PeriodicalIF":3.5,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsmedchemlett.5c00338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587258","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}
引用次数: 0
Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule 利用水分子置换优化肽精氨酸脱亚胺酶抑制剂
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-09 DOI: 10.1021/acsmedchemlett.5c00372
Mark E. Schnute*, Gary M. Chinigo*, Kentaro Futatsugi, Masaya Yamaguchi, Scott W. Bagley, Mary Ellen Banker, Jeanne S. Chang, Ming Z. Chen, Won Young Choi, Matthew S. Corbett, Susan E. Drozda, David C. Ebner, Carmen Garcia-Irizarry, Robert Hicklin, Susan Hoy, Wenhua Jiao, Steven Kortum, Katherine L. Lee, David C. Limburg, Frank Lovering, Antonio Moreno, James J. Mousseau, Senliang Pan, Mihir D. Parikh, Jeffrey W. Pelker, Simeon Ramsey, Usa Reilly, Gwenaella Rescourio, Daniel C. Schmitt, Brittany Simpson, Grzegorz J. Skrzypek, Daniel J. Smaltz, Alexandria P. Taylor, Rubben Torella, John I. Trujillo, Felix F. Vajdos, James A. Wepy, Stephen W. Wright, David C. Blakemore, Fabien Vincent and Valerie M. Clerin, 
{"title":"Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule","authors":"Mark E. Schnute*,&nbsp;Gary M. Chinigo*,&nbsp;Kentaro Futatsugi,&nbsp;Masaya Yamaguchi,&nbsp;Scott W. Bagley,&nbsp;Mary Ellen Banker,&nbsp;Jeanne S. Chang,&nbsp;Ming Z. Chen,&nbsp;Won Young Choi,&nbsp;Matthew S. Corbett,&nbsp;Susan E. Drozda,&nbsp;David C. Ebner,&nbsp;Carmen Garcia-Irizarry,&nbsp;Robert Hicklin,&nbsp;Susan Hoy,&nbsp;Wenhua Jiao,&nbsp;Steven Kortum,&nbsp;Katherine L. Lee,&nbsp;David C. Limburg,&nbsp;Frank Lovering,&nbsp;Antonio Moreno,&nbsp;James J. Mousseau,&nbsp;Senliang Pan,&nbsp;Mihir D. Parikh,&nbsp;Jeffrey W. Pelker,&nbsp;Simeon Ramsey,&nbsp;Usa Reilly,&nbsp;Gwenaella Rescourio,&nbsp;Daniel C. Schmitt,&nbsp;Brittany Simpson,&nbsp;Grzegorz J. Skrzypek,&nbsp;Daniel J. Smaltz,&nbsp;Alexandria P. Taylor,&nbsp;Rubben Torella,&nbsp;John I. Trujillo,&nbsp;Felix F. Vajdos,&nbsp;James A. Wepy,&nbsp;Stephen W. Wright,&nbsp;David C. Blakemore,&nbsp;Fabien Vincent and Valerie M. Clerin,&nbsp;","doi":"10.1021/acsmedchemlett.5c00372","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00372","url":null,"abstract":"<p >Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Protein citrullination is mediated by the peptidylarginine deiminase enzyme family (PAD1–4), and inhibition of one or several PAD isozymes in combination may offer a therapeutic approach to targeting these diseases. Building upon the discovery of PAD–PF2, an allosteric inhibitor of PAD1–4, herein, we report on the optimization of potency and pharmacokinetic properties while minimizing hERG channel liabilities within this novel chemical series. Through structure-based ligand design, a structural water was successfully displaced, allowing expansion of the ligand binding site and access to a previously unexplored hydrophobic pocket resulting in a 10-fold improvement in potency. Compound <b>4f</b> demonstrated potent inhibition of PAD-mediated citrullination in human and rat neutrophils, reduced hERG channel liabilities, and good oral bioavailability in preclinical animal species.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1662–1669"},"PeriodicalIF":4.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826122","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}
引用次数: 0
Novel Heterocyclic Compounds as 5-HT2C Agonists for Treating Depression, Drug Addiction, Alcoholism, PTSD and Neuropathic Pain 新型杂环化合物作为5-HT2C激动剂治疗抑郁症、药物成瘾、酒精中毒、创伤后应激障碍和神经性疼痛
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-09 DOI: 10.1021/acsmedchemlett.5c00400
Ram W. Sabnis*, 
{"title":"Novel Heterocyclic Compounds as 5-HT2C Agonists for Treating Depression, Drug Addiction, Alcoholism, PTSD and Neuropathic Pain","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00400","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00400","url":null,"abstract":"<p >Provided herein are novel heterocyclic compounds as 5-HT2C agonists, pharmaceutical compositions, use of such compounds in treating depression, drug addiction, alcoholism, post-traumatic stress disorder (PTSD) and neuropathic pain and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1488–1489"},"PeriodicalIF":4.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826106","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}
引用次数: 0
Novel Compounds as 5-HT2A Agonists for Treating Mental Illness or CNS Disorders 新化合物作为5-HT2A激动剂治疗精神疾病或中枢神经系统疾病
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-09 DOI: 10.1021/acsmedchemlett.5c00399
Ram W. Sabnis*, 
{"title":"Novel Compounds as 5-HT2A Agonists for Treating Mental Illness or CNS Disorders","authors":"Ram W. Sabnis*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00399","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00399","url":null,"abstract":"<p >Provided herein are novel compounds as 5-HT2A agonists, pharmaceutical compositions, use of such compounds in treating mental illness or CNS disorders and processes for preparing such compounds.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1490–1491"},"PeriodicalIF":4.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826128","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}
引用次数: 0
Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor 新一代强效镰状血红蛋白聚合抑制剂Osivelotor的发现
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-08 DOI: 10.1021/acsmedchemlett.5c00076
Zhe Li, Carsten Alt, Kobina Dufu, Athiwat Hutchaleelaha, Qing Xu, Xinchun Zhang, Chien-Ming Li, Peter Rademacher, Caroline Bosmajian, Mira Patel Pochron, James R. Partridge, Donna Oksenberg and Brian E. Cathers*, 
{"title":"Discovery of Osivelotor (GBT021601): A Potent, Next-Generation Sickle Hemoglobin Polymerization Inhibitor","authors":"Zhe Li,&nbsp;Carsten Alt,&nbsp;Kobina Dufu,&nbsp;Athiwat Hutchaleelaha,&nbsp;Qing Xu,&nbsp;Xinchun Zhang,&nbsp;Chien-Ming Li,&nbsp;Peter Rademacher,&nbsp;Caroline Bosmajian,&nbsp;Mira Patel Pochron,&nbsp;James R. Partridge,&nbsp;Donna Oksenberg and Brian E. Cathers*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00076","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00076","url":null,"abstract":"<p >This report details the discovery path of GBT021601 (osivelotor) (<b>16</b>), a novel, small molecule, sickle hemoglobin (HbS) polymerization inhibitor. Following a streamlined testing funnel with cassette dosing in rat pharmacokinetic (PK) studies, we identified this next-generation HbS polymerization inhibitor, which had improved PK properties compared with the first-in-class drug, voxelotor (<b>1</b>). GBT021601 has ∼4.8-fold greater exposure and a ∼3.5-fold longer half-life in rats compared with voxelotor. In a murine model of sickle cell disease (SCD), GBT021601 treatment resulted in an increase in hemoglobin oxygen affinity, a reduction in sickling of red blood cells (RBCs), and an increase in both RBC half-life and hemoglobin levels not seen with voxelotor preclinically. The improved half-life and exposure appear to translate to similar levels of HbS occupancy at lower doses than voxelotor, thus reducing treatment burden. GBT021601 is being investigated in a phase 2/3 clinical trial for the treatment of patients with SCD (NCT05431088).</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1526–1532"},"PeriodicalIF":4.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826104","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}
引用次数: 0
Property-Based Optimization of Cereblon-Based Molecular Glue Degraders 基于cereblon的分子胶降解剂性能优化
IF 4 3区 医学
ACS Medicinal Chemistry Letters Pub Date : 2025-07-08 DOI: 10.1021/acsmedchemlett.5c00308
Lyn H. Jones*, 
{"title":"Property-Based Optimization of Cereblon-Based Molecular Glue Degraders","authors":"Lyn H. Jones*,&nbsp;","doi":"10.1021/acsmedchemlett.5c00308","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00308","url":null,"abstract":"<p >Molecular glue degraders that bind the E3 ligase adaptor cereblon are clinically precedented drugs used to treat cancer. Highly potent next-generation degraders are in development that target difficult-to-drug neosubstrates, such as transcription factors, for several different indications. This Microperspective covers the medicinal chemistry strategies being used to advance the property-based optimization of cereblon-based molecular glue degraders through consideration of their physicochemical characteristics.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 8","pages":"1456–1462"},"PeriodicalIF":4.0,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144826105","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}
引用次数: 0
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