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Interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors: an updated patent review (2016-2018).白细胞介素-1 受体相关激酶 4（IRAK4）抑制剂：更新的专利审查（2016-2018 年）。
Expert Opin Ther Pat. 2019 Apr;29(4):243-259. doi: 10.1080/13543776.2019.1597850. Epub 2019 Mar 29.
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Discovery and structure-based design of 4,6-diaminonicotinamides as potent and selective IRAK4 inhibitors.基于结构设计发现4,6-二氨基烟酰胺作为有效的选择性IRAK4抑制剂。
Bioorg Med Chem Lett. 2017 Nov 1;27(21):4908-4913. doi: 10.1016/j.bmcl.2017.09.029. Epub 2017 Sep 18.
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Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design.通过基于片段的药物设计发现临床候选药物1-{[(2S,3S,4S)-3-乙基-4-氟-5-氧代吡咯烷-2-基]甲氧基}-7-甲氧基异喹啉-6-甲酰胺（PF-06650833），一种有效的白细胞介素-1受体相关激酶4（IRAK4）选择性抑制剂。
J Med Chem. 2017 Jul 13;60(13):5521-5542. doi: 10.1021/acs.jmedchem.7b00231. Epub 2017 Jun 14.
4
Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity.选择性抑制IRAK4可减轻小鼠狼疮模型中的疾病并显示出激素节省活性。
J Immunol. 2017 Feb 1;198(3):1308-1319. doi: 10.4049/jimmunol.1600583. Epub 2016 Dec 21.
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Applications of Fluorine in Medicinal Chemistry.氟在药物化学中的应用。
J Med Chem. 2015 Nov 12;58(21):8315-59. doi: 10.1021/acs.jmedchem.5b00258. Epub 2015 Jul 22.
6
Lck and the nature of the T cell receptor trigger.Lck 和 T 细胞受体触发的本质。
Trends Immunol. 2011 Jan;32(1):1-5. doi: 10.1016/j.it.2010.11.003. Epub 2010 Dec 27.
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Analysis of kinase inhibitor selectivity using a thermodynamics-based partition index.基于热力学分配指数分析激酶抑制剂的选择性。
J Med Chem. 2010 Jun 10;53(11):4502-10. doi: 10.1021/jm100301x.
8
The critical role of kinase activity of interleukin-1 receptor-associated kinase 4 in animal models of joint inflammation.白细胞介素-1受体相关激酶4的激酶活性在关节炎症动物模型中的关键作用。
Arthritis Rheum. 2009 Jun;60(6):1661-71. doi: 10.1002/art.24552.
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The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress.白细胞介素-1受体/Toll样受体超家族：十年进展
Immunol Rev. 2008 Dec;226:10-8. doi: 10.1111/j.1600-065X.2008.00701.x.
10
Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity.IRAK-4缺陷儿童对细菌感染的选择性易感性：依赖IRAK-4的Toll样受体在保护性免疫中原本是多余的。
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烟酰胺作为强效且选择性的白细胞介素-1受体相关激酶4（IRAK4）抑制剂的优化及其在银屑病小鼠模型中的疗效

Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.

作者信息

Nair Satheesh, Kumar Sreekantha Ratna, Paidi Venkatram Reddy, Sistla Ramesh, Kantheti Durgarao, Polimera Subba Rao, Thangavel Soodamani, Mukherjee Amrita Jha, Das Mitalee, Bhide Rajeev S, Pitts William J, Murugesan Natesan, Dudhgoankar Shailesh, Nagar Jignesh, Subramani Siva, Mazumder Debarati, Carman Julie A, Holloway Deborah A, Li Xin, Fereshteh Mark P, Ruepp Stefan, Palanisamy Kamalavenkatesh, Mariappan T Thanga, Maddi Srinivas, Saxena Ajay, Elzinga Paul, Chimalakonda Anjaneya, Ruan Qian, Ghosh Kaushik, Bose Sucharita, Sack John, Yan Chunhong, Kiefer Susan E, Xie Dianlin, Newitt John A, Saravanakumar S Pon, Rampulla Richard A, Barrish Joel C, Carter Percy H, Hynes John

机构信息

Biocon Bristol Myers Squibb Research Center, Bangalore 560099, India.

Research & Development, Bristol Myers Squibb, Route 206 & Province Line Road, Princeton, New Jersey 08543, United States.

出版信息

ACS Med Chem Lett. 2020 Jun 10;11(7):1402-1409. doi: 10.1021/acsmedchemlett.0c00082. eCollection 2020 Jul 9.

DOI:10.1021/acsmedchemlett.0c00082
PMID:32676146
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7357863/
Abstract

IRAK4 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as with improved potency and selectivity. Additionally demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective , which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.

摘要

IRAK4是治疗炎症性疾病的一个有吸引力的治疗靶点。烟酰胺系列抑制剂的结构导向优化已扩展到探索IRAK4前口袋。这导致了如具有提高的效力和选择性的化合物的鉴定。此外，在药代动力学/药效学（PK/PD）模型中显示出活性。进一步的优化努力导致了高度激酶组选择性的鉴定，其在小鼠银屑病的TLR7驱动模型中显示出强大的PD效应和疗效。