ACS Medicinal Chemistry Letters最新文献_第7页

Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-06 eCollection Date: 2024-12-12 DOI: 10.1021/acsmedchemlett.4c00401

Ross P Hryczanek, Andrew S Hackett, Paul Rowland, Chun-Wa Chung, Máire A Convery, Duncan S Holmes, Jonathan P Hutchinson, Semra Kitchen, Justyna Korczynska, Robert P Law, Jonathan D Lea, John Liddle, Richard Lonsdale, Margarete Neu, Leng Nickels, Alex Phillipou, James E Rowedder, Jessica L Schneck, Paul Scott-Stevens, Hester Sheehan, Chloe L Tayler, Ioannis Temponeras, Christopher P Tinworth, Ann L Walker, Justyna Wojno-Picon, Robert J Young, David M Lindsay, Efstratios Stratikos

{"title":"Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.","authors":"Ross P Hryczanek, Andrew S Hackett, Paul Rowland, Chun-Wa Chung, Máire A Convery, Duncan S Holmes, Jonathan P Hutchinson, Semra Kitchen, Justyna Korczynska, Robert P Law, Jonathan D Lea, John Liddle, Richard Lonsdale, Margarete Neu, Leng Nickels, Alex Phillipou, James E Rowedder, Jessica L Schneck, Paul Scott-Stevens, Hester Sheehan, Chloe L Tayler, Ioannis Temponeras, Christopher P Tinworth, Ann L Walker, Justyna Wojno-Picon, Robert J Young, David M Lindsay, Efstratios Stratikos","doi":"10.1021/acsmedchemlett.4c00401","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00401","url":null,"abstract":"Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the N-terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease. Herein we describe the hit-to-lead optimization of a series of cyclohexyl acid ERAP1 inhibitors, found by X-ray crystallography to bind at an allosteric regulatory site. Structure-based drug design enabled a >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound 7, rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 12","pages":"2107-2114"},"PeriodicalIF":3.5,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11647717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142845288","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

Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors 作为新型表皮生长因子受体抑制剂的 3-氨基吡嗪-2-甲酰胺衍生物的设计、合成和生物学评价

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-05 DOI: 10.1021/acsmedchemlett.4c0043110.1021/acsmedchemlett.4c00431

Jia Zheng, Wei Zhang, Dan Ni, Shuang Zhao, Yi He, Junchi Hu, Linfeng Li, Yongjun Dang, Zufeng Guo* and Shenyou Nie*,

引用次数: 0

Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors. 作为新型表皮生长因子受体抑制剂的 3-氨基吡嗪-2-甲酰胺衍生物的设计、合成和生物学评价。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-05 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00431

Jia Zheng, Wei Zhang, Dan Ni, Shuang Zhao, Yi He, Junchi Hu, Linfeng Li, Yongjun Dang, Zufeng Guo, Shenyou Nie

引用次数: 0

Azaspirooctane-carboxylates as Novel Activators/Modulators of M4 for the Treatment of Alzheimer’s Disease and Parkinson’s Disease 作为治疗阿尔茨海默病和帕金森病的新型 M4 激活剂/调节剂的氮杂环辛烷羧酸盐

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-04 DOI: 10.1021/acsmedchemlett.4c0051210.1021/acsmedchemlett.4c00512

Gerard Rosse*,

引用次数: 0

Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria 发现作为高草酸尿症草酸钙结晶抑制剂的 l-赖氨酸二噁醛酸盐 (LH1513)

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-04 DOI: 10.1021/acsmedchemlett.4c0042310.1021/acsmedchemlett.4c00423

Longqin Hu*, Akash Taneja, Husam Zahid, Yiling Wang, Min Yang, Zhihua An, Xingsheng Li, Jay A. Tischfield, John Knight, Michael D. Ward and Amrik Sahota,

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引用次数: 0

Novel Aminopyrazole Inhibitors of PDE11A for the Treatment of Alzheimer's Disease and Other Types of Dementia. 用于治疗阿尔茨海默病和其他类型痴呆症的新型 PDE11A 氨基吡唑抑制剂。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-04 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00513

Gerard Rosse

引用次数: 0

Azaspirooctane-carboxylates as Novel Activators/Modulators of M4 for the Treatment of Alzheimer's Disease and Parkinson's Disease. 作为治疗阿尔茨海默病和帕金森病的新型 M4 激活剂/调节剂的氮杂环辛烷羧酸盐。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-04 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00512

Gerard Rosse

引用次数: 0

Novel Aminopyrazole Inhibitors of PDE11A for the Treatment of Alzheimer’s Disease and Other Types of Dementia 用于治疗阿尔茨海默病和其他类型痴呆症的新型氨基吡唑 PDE11A 抑制剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-04 DOI: 10.1021/acsmedchemlett.4c0051310.1021/acsmedchemlett.4c00513

Gerard Rosse*,

引用次数: 0

Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria. 发现作为高草酸尿症草酸钙结晶抑制剂的 l-赖氨酸二噁醛酸盐 (LH1513)。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-04 eCollection Date: 2024-11-14 DOI: 10.1021/acsmedchemlett.4c00423

Longqin Hu, Akash Taneja, Husam Zahid, Yiling Wang, Min Yang, Zhihua An, Xingsheng Li, Jay A Tischfield, John Knight, Michael D Ward, Amrik Sahota

{"title":"Discovery of l-Lysine Dioxalate (LH1513) as a Novel Inhibitor of Calcium Oxalate Crystallization for Hyperoxaluria.","authors":"Longqin Hu, Akash Taneja, Husam Zahid, Yiling Wang, Min Yang, Zhihua An, Xingsheng Li, Jay A Tischfield, John Knight, Michael D Ward, Amrik Sahota","doi":"10.1021/acsmedchemlett.4c00423","DOIUrl":"10.1021/acsmedchemlett.4c00423","url":null,"abstract":"Hyperoxaluria is caused by increased urinary excretion of oxalate leading to the formation of calcium oxalate (CaOx) stones. The lack of effective management strategies for hyperoxaluria prompted us to investigate molecular mimics as stone inhibitors, a strategy that we previously used successfully to discover small molecule inhibitors of l-cystine crystallization for the prevention of l-cystine stone formation in cystinuria. Herein, we report the discovery of l-lysine dioxalate (LH1513), a novel dioxamate derivative, as a more potent inhibitor of CaOx crystallization than citrate and pyruvate. Such inhibition was corroborated by in situ atomic force microscopy (AFM) measurements of crystal growth rates at the microscopic length scale. A triester prodrug of LH1513 was found to have sufficient oral bioavailability for a preliminary in vivo study demonstrating efficacy in preventing urinary CaOx crystal formation in an Agxt-knockout mouse model for hyperoxaluria.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"2005-2011"},"PeriodicalIF":3.5,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674522","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

Peptide Aldehydes Incorporating Thiazol-4-yl Alanine Are Potent In Vitro Inhibitors of SARS-CoV-2 Main Protease 含有噻唑-4-基丙氨酸的肽醛是 SARS-CoV-2 主要蛋白酶的强效体外抑制剂

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2024-11-03 DOI: 10.1021/acsmedchemlett.4c0044410.1021/acsmedchemlett.4c00444

Jenson R. Feys, Kyle Edwards, Michael A. Joyce, Holly A. Saffran, Justin A. Shields, Kassandra Garcia, D. Lorne Tyrrell and Conrad Fischer*,

{"title":"Peptide Aldehydes Incorporating Thiazol-4-yl Alanine Are Potent In Vitro Inhibitors of SARS-CoV-2 Main Protease","authors":"Jenson R. Feys, Kyle Edwards, Michael A. Joyce, Holly A. Saffran, Justin A. Shields, Kassandra Garcia, D. Lorne Tyrrell and Conrad Fischer*, ","doi":"10.1021/acsmedchemlett.4c0044410.1021/acsmedchemlett.4c00444","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00444https://doi.org/10.1021/acsmedchemlett.4c00444","url":null,"abstract":"The main protease of SARS-CoV-2 is an essential enzyme required for polyprotein cleavage during viral replication and thus is an excellent target for development of direct-acting antiviral compounds. Continued research efforts have elucidated several peptidic small molecules like GC376, boceprevir, and nirmatrelvir with potent anticoronaviral activity bearing optimized amino acid side chain residues. To reduce synthetic complexity and cost, we used simple chemical surrogates that were commercially readily available to develop new inhibitors that mimic the potency of these drug compounds. We synthesized and tested several analogue chimeras of GC376 and boceprevir that have surrogate residues at the P1 and/or P2 position in order to further improve target binding. Both P1 variants with either a nonpolar cyclobutyl or polar thiazol-4-yl alanine resulted in low-micromolar to submicromolar Mpro inhibitors with strong antiviral activity in cell assays.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"15 11","pages":"2046–2052 2046–2052"},"PeriodicalIF":3.5,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640749","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