ACS Medicinal Chemistry Letters最新文献

In This Issue, Volume 16, Issue 4 见本刊第16卷第4期

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-05-08 DOI: 10.1021/acsmedchemlett.5c0015110.1021/acsmedchemlett.5c00151

Andrew P. Riley,

引用次数: 0

In this Issue, Volume 16, Issue 5 本刊第16卷第5期

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-05-08 DOI: 10.1021/acsmedchemlett.5c0022310.1021/acsmedchemlett.5c00223

Amanda W. Dombrowski,

引用次数: 0

Design, Synthesis, and Evaluation of Sodium Channel Blockers with Anti-invasive Activities in Medullary Thyroid Cancer. 抗甲状腺髓样癌侵袭性钠通道阻滞剂的设计、合成和评价。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-29 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.4c00576

Piyasuda Pukkanasut, Shilpa Dutta, Jason Whitt, Parvathy Babu, Osbaldo Lopez-Charcas, Tonantzin Guadalupe Anguheven-Ledezma, Juan Carlos Gomora, Renata Jaskula-Sztul, Sadanandan E Velu

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引用次数: 0

IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia. IRAK1/4/pan-FLT3激酶抑制剂减少hERG阻滞治疗急性髓性白血病

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-29 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00147

Scott B Hoyt, Chris J Finocchio, Elizabeth Croll, Gregory J Tawa, Mingliang Zhang, Jiangong Wang, Huixi Li, Li Ma, Kaikai Li, Xiaohu Zhang, Xin Xu, Pranav Shah, Yuhong Fang, Lyndsey C Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F Edmondson, Simone Difilippantonio, LaQuita M Jones, Ashley E Culver-Cochran, Jan S Rosenbaum, Daniel T Starczynowski, Craig J Thomas

引用次数: 0

Design, Synthesis, and Evaluation of Sodium Channel Blockers with Anti-invasive Activities in Medullary Thyroid Cancer 抗甲状腺髓样癌侵袭性钠通道阻滞剂的设计、合成和评价

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI: 10.1021/acsmedchemlett.4c0057610.1021/acsmedchemlett.4c00576

Piyasuda Pukkanasut, Shilpa Dutta, Jason Whitt, Parvathy Babu, Osbaldo Lopez-Charcas, Tonantzin Guadalupe Anguheven-Ledezma, Juan Carlos Gomora, Renata Jaskula-Sztul* and Sadanandan E. Velu*,

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引用次数: 0

IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia IRAK1/4/pan-FLT3激酶抑制剂减少hERG阻滞治疗急性髓性白血病

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-29 DOI: 10.1021/acsmedchemlett.5c0014710.1021/acsmedchemlett.5c00147

Scott B. Hoyt*, Chris J. Finocchio, Elizabeth Croll, Gregory J. Tawa, Mingliang Zhang, Jiangong Wang, Huixi Li, Li Ma, Kaikai Li, Xiaohu Zhang, Xin Xu, Pranav Shah, Yuhong Fang, Lyndsey C. Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F. Edmondson, Simone Difilippantonio, LaQuita M. Jones, Ashley E. Culver-Cochran, Jan S. Rosenbaum, Daniel T. Starczynowski and Craig J. Thomas,

{"title":"IRAK1/4/pan-FLT3 Kinase Inhibitors with Reduced hERG Block as Treatments for Acute Myeloid Leukemia","authors":"Scott B. Hoyt*, Chris J. Finocchio, Elizabeth Croll, Gregory J. Tawa, Mingliang Zhang, Jiangong Wang, Huixi Li, Li Ma, Kaikai Li, Xiaohu Zhang, Xin Xu, Pranav Shah, Yuhong Fang, Lyndsey C. Bolanos, Gabriel Gracia-Maldonado, Amal Kolt, Christina Robinson, Jessica Free, Elijah F. Edmondson, Simone Difilippantonio, LaQuita M. Jones, Ashley E. Culver-Cochran, Jan S. Rosenbaum, Daniel T. Starczynowski and Craig J. Thomas, ","doi":"10.1021/acsmedchemlett.5c0014710.1021/acsmedchemlett.5c00147","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00147https://doi.org/10.1021/acsmedchemlett.5c00147","url":null,"abstract":"We report the optimization of a series of IRAK1/4/pan-FLT3 kinase inhibitors. These efforts have produced a key compound 27 that displays potent and selective inhibition of IRAK1, IRAK4, and FLT3, reduced block of hERG, and good pharmacokinetic properties. In a mouse xenograft model of acute myeloid leukemia (AML), 27 produces survival prolongation superior to that of gilteritinib, the leading FDA-approved FLT3 inhibitor currently used to treat AML.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"887–895 887–895"},"PeriodicalIF":3.5,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.5c00147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143917010","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

Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor in Vivo Tool Compound. ONO-TR-772 (VU6018042)：一种高选择性和中枢神经系统渗透的TREK抑制剂体内工具化合物的发现。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-28 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00215

Motoyuki Tanaka, Takahiro Mori, Gakuji Hashimoto, Katsukuni Mitsui, Akihiro Kishi, Elizabeth S Childress, Sean R Bollinger, Trevor C Chopko, Thomas M Bridges, Douglas G Stafford, Zhonping Huang, Mark A Wolf, Darren W Engers, Jerod S Denton, Haruto Kurata, Craig W Lindsley

{"title":"Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor in Vivo Tool Compound.","authors":"Motoyuki Tanaka, Takahiro Mori, Gakuji Hashimoto, Katsukuni Mitsui, Akihiro Kishi, Elizabeth S Childress, Sean R Bollinger, Trevor C Chopko, Thomas M Bridges, Douglas G Stafford, Zhonping Huang, Mark A Wolf, Darren W Engers, Jerod S Denton, Haruto Kurata, Craig W Lindsley","doi":"10.1021/acsmedchemlett.5c00215","DOIUrl":"10.1021/acsmedchemlett.5c00215","url":null,"abstract":"Herein we describe our continuing work on the K2P family of potassium ion channels with the chemical optimization of a selective and CNS penetrant series of TREK inhibitors, culminating in the discovery of ONO-TR-772 (VU6018042). From an HTS hit harboring a benzyl ether linker, SAR proved intractable until an acetylene linker was identified as an isosteric replacement. Robust SAR was then observed, and a key fluorination to enhance PK and CNS penetration provided ONO-TR-772 (VU6018042), a potent (TREK-1 IC50 = 15 nM), selective (>10 μM versus other K2P channels except TREK-2), and CNS penetrant (rat K p = 0.98) TREK inhibitor. ONO-TR-772 (VU6018042) demonstrated robust efficacy in an MK-801 challenge NOR paradigm, with an MED of 10 mg/kg.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"896-901"},"PeriodicalIF":3.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951975","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

Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor in Vivo Tool Compound ONO-TR-772 (VU6018042)：一种高选择性和中枢神经系统渗透的TREK抑制剂体内工具化合物的发现

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-28 DOI: 10.1021/acsmedchemlett.5c0021510.1021/acsmedchemlett.5c00215

Motoyuki Tanaka, Takahiro Mori, Gakuji Hashimoto, Katsukuni Mitsui, Akihiro Kishi, Elizabeth S. Childress, Sean R. Bollinger, Trevor C. Chopko, Thomas M. Bridges, Douglas G. Stafford, Zhonping Huang, Mark A. Wolf, Darren W. Engers, Jerod S. Denton, Haruto Kurata* and Craig W. Lindsley*,

{"title":"Discovery of ONO-TR-772 (VU6018042): A Highly Selective and CNS Penetrant TREK Inhibitor in Vivo Tool Compound","authors":"Motoyuki Tanaka, Takahiro Mori, Gakuji Hashimoto, Katsukuni Mitsui, Akihiro Kishi, Elizabeth S. Childress, Sean R. Bollinger, Trevor C. Chopko, Thomas M. Bridges, Douglas G. Stafford, Zhonping Huang, Mark A. Wolf, Darren W. Engers, Jerod S. Denton, Haruto Kurata* and Craig W. Lindsley*, ","doi":"10.1021/acsmedchemlett.5c0021510.1021/acsmedchemlett.5c00215","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00215https://doi.org/10.1021/acsmedchemlett.5c00215","url":null,"abstract":"Herein we describe our continuing work on the K2P family of potassium ion channels with the chemical optimization of a selective and CNS penetrant series of TREK inhibitors, culminating in the discovery of ONO-TR-772 (VU6018042). From an HTS hit harboring a benzyl ether linker, SAR proved intractable until an acetylene linker was identified as an isosteric replacement. Robust SAR was then observed, and a key fluorination to enhance PK and CNS penetration provided ONO-TR-772 (VU6018042), a potent (TREK-1 IC50 = 15 nM), selective (>10 μM versus other K2P channels except TREK-2), and CNS penetrant (rat Kp = 0.98) TREK inhibitor. ONO-TR-772 (VU6018042) demonstrated robust efficacy in an MK-801 challenge NOR paradigm, with an MED of 10 mg/kg.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 5","pages":"896–901 896–901"},"PeriodicalIF":3.5,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.5c00215","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916969","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

Novel Compounds as NLRP3 Inhibitors for Treating Asthma or COPD 新化合物作为NLRP3抑制剂治疗哮喘或COPD

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-26 DOI: 10.1021/acsmedchemlett.5c0021810.1021/acsmedchemlett.5c00218

Ram W. Sabnis*,

引用次数: 0

Novel Compounds as NLRP3 Inhibitors for Treating Asthma or COPD. 新化合物作为NLRP3抑制剂治疗哮喘或COPD

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-04-26 eCollection Date: 2025-05-08 DOI: 10.1021/acsmedchemlett.5c00218

Ram W Sabnis

引用次数: 0