{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:37:51Z","timestamp":1789713471183,"version":"4.0.1"},"reference-count":35,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-017"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-012"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-004"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Bioorganic &amp; Medicinal Chemistry"],"published-print":{"date-parts":[[2025,12]]},"DOI":"10.1016\/j.bmc.2025.118333","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T23:27:45Z","timestamp":1753745265000},"page":"118333","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":3,"special_numbering":"C","title":["Generation of a potent &amp; selective series of IRAK4 inhibitors based on a structure based, hybridization approach"],"prefix":"10.1016","volume":"131","author":[{"given":"Ina","family":"Terstiege","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Aagaard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Berggren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Bird","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iain A.","family":"Cumming","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam D.","family":"Groombridge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotta","family":"Hidest\u00e5l","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Johannesson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pernilla","family":"Korsgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl-Johan","family":"Leuchowius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Lundqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James S.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yafeng","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien L.","family":"Degorce","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.bmc.2025.118333_bb0005","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.bcp.2010.06.020","article-title":"The interleukin-1 receptor-associated kinases: critical regulators of innate immune signalling","volume":"80","author":"Flannery","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"10.1016\/j.bmc.2025.118333_bb0010","doi-asserted-by":"crossref","first-page":"724","DOI":"10.2174\/156802609789044407","article-title":"IRAK-4 inhibitors for inflammation","volume":"9","author":"Wang","year":"2009","journal-title":"Curr. Top. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0015","doi-asserted-by":"crossref","first-page":"5521","DOI":"10.1021\/acs.jmedchem.7b00231","volume":"60","author":"Lee","year":"2017","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0020","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1021\/acs.jmedchem.3c01714","article-title":"Discovery of IRAK4 inhibitors BAY1834845 (Zabedosertib) and BAY1830839","volume":"67","author":"Bothe","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0025","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejmech.2023.115606","article-title":"The recent advance of Interleukin-1 receptor associated kinase 4 inhibitors for the treatment of inflammation and related diseases","volume":"258","author":"Bai","year":"2023","journal-title":"Eur J Med Chem"},{"key":"10.1016\/j.bmc.2025.118333_bb0030","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1097\/MOH.0000000000000693","article-title":"IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies","volume":"29","author":"Bennett","year":"2022","journal-title":"Curr Opin Hematol."},{"key":"10.1016\/j.bmc.2025.118333_bb0035","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1084\/jem.20070628","article-title":"Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity","volume":"204","author":"Ku","year":"2007","journal-title":"J. Exp. Med."},{"key":"10.1016\/j.bmc.2025.118333_bb0040","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.1021\/acsmedchemlett.0c00255","article-title":"Discovery of CA-4948, an orally bioavailable IRAK4 inhibitor for treatment of hematologic malignancies","volume":"11","author":"Gummadi","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"10.1016\/j.bmc.2025.118333_bb0045","doi-asserted-by":"crossref","unstructured":"Ammann SE, Cottell JJ, Wright NE, Warr MR, Snyder CA, Bacon EM, Brizgys G, Chin E, Chou C, Conway A, Dick RA, Ferrao RD, Garrison KL, Hammond A, Lansdon EB, Link JO, Mukherjee PK, Murray BP, Mwangi J, Ndukwe MS, Park GY, Serone AP, Suekawa-Pirrone K, Yang ZY, Zipfel SM, Taylor JG. Discovery of Edecesertib (GS-5718): A potent, selective inhibitor of IRAK4. J Med Chem 2025; 68: in press. Doi: https:\/\/doi.org\/10.1021\/acs.jmedchem.5c00463.","DOI":"10.1021\/acs.jmedchem.5c00463"},{"key":"10.1016\/j.bmc.2025.118333_bb0050","unstructured":"Chou L, Fuan M, Darwish I, Shaw S, Bhamidipati S, Taylor V, Chen Y, Fan D, Luo Z. A method for treating a disease or condition using a pyrazole compound or formulation thereof. WO2022187303, September 09, 2022. Accessed November 1, 2024. https:\/\/patentscope.wipo.int\/search\/en\/detail.jsf?docId=WO2022187303."},{"key":"10.1016\/j.bmc.2025.118333_bb0055","unstructured":"Safety and efficacy of PF-06650833 in subjects with rheumatoid arthritis, with an inadequate response to methotrexate. ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02996500."},{"key":"10.1016\/j.bmc.2025.118333_bb0060","unstructured":"A study to evaluate the safety and efficacy of PF-06650833, PF-06700841, and PF-06826647 in adults with hidradenitis suppurativa. ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04092452."},{"key":"10.1016\/j.bmc.2025.118333_bb0065","unstructured":"A study of CA-4948 in patients with relapsed or refractory primary central nervous system lymphoma. ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03328078."},{"key":"10.1016\/j.bmc.2025.118333_bb0070","unstructured":"Dose Escalation\/ Expansion study of CA-4948 as monotherapy in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04278768."},{"key":"10.1016\/j.bmc.2025.118333_bb0075","unstructured":"Study of edecesertib in participants with cutaneous lupus erythematosus (CLE). ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04809623."},{"key":"10.1016\/j.bmc.2025.118333_bb0080","unstructured":"A trial to learn how BAY1834845 and BAY1830839 affect inflammation when taken by mouth twice a day for 7 days in a row in healthy male participants. ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05003089."},{"key":"10.1016\/j.bmc.2025.118333_bb0085","unstructured":"A multiple dose study of BAY1834845 in healthy male subjects and in patients with psoriasis. ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03493269."},{"key":"10.1016\/j.bmc.2025.118333_bb0090","unstructured":"A study to learn how well the study treatment Zabedosertib (BAY1834845) works and how safe it is compared to placebo in adult participants with moderate-to-severe atopic dermatitis (Damask). ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05656911."},{"key":"10.1016\/j.bmc.2025.118333_bb0095","unstructured":"Study of R289 in participants with lower-risk myelodysplastic syndromes (LR-MDS). ClinicalTrials.gov. Accessed July 26, 2024. https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05308264."},{"key":"10.1016\/j.bmc.2025.118333_bb0100","doi-asserted-by":"crossref","unstructured":"Nair S, Kumar SR, Paidi VR, Sistla R, Kantheti D, Polimera SR, Thangavel S, Mukherjee AJ, Das M, Bhide RS, Pitts WJ, Murugesan N, Dudhgoankar S, Nagar J, Subramani S, Mazumder D, Carman JA, Holloway DA, Li Z, Fereshteh MP, Ruepp S, Palanisamy K, Mariappan TT, Maddi S, Saxena Ajay, Elzinga P, Chimalakonda A, Ruan Q, Ghosh K, Bose S, Sack J, Yan C, Kiefer SE, Xie D, Newitt JA, SaravanakumarSP, Rampulla RA, Barrish JC, Carter PH, Hynes Jr, J. Optimization of nicotinamides as potent and selective IRAK4 inhibitors with efficacy in a murine model of psoriasis. ACS Med. Chem. Lett. 2020; 11:1401\u20131409. Doi: https:\/\/doi.org\/10.1021\/acsmedchemlett.0c00082.","DOI":"10.1021\/acsmedchemlett.0c00082"},{"key":"10.1016\/j.bmc.2025.118333_bb0105","doi-asserted-by":"crossref","first-page":"6223","DOI":"10.1021\/acs.jmedchem.9b00439","article-title":"Development of potent and selective Pyrazolopyrimidine IRAK4 inhibitors","volume":"62","author":"Bryan","year":"2019","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0110","doi-asserted-by":"crossref","DOI":"10.1016\/j.bmc.2023.117302","article-title":"Design, synthesis, and pharmacological evaluation of N-(3-carbamoyl-1H\u2014pyrazole-4-yl)-1,3-oxazole-4-carboxamide derivatives as interleukin-1 receptor-associated kinase 4 inhibitors with reduced potential for cytochrome P450 1A2 induction","volume":"87","author":"Inami","year":"2023","journal-title":"Biorg. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0115","doi-asserted-by":"crossref","first-page":"4676","DOI":"10.1021\/acs.jmedchem.3c02226","article-title":"The discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicuclo[2.1.1]hexan-4-yl)-N-(6-methylpyrazolo[1,5-a]pyrimidin-3-yl)imidazo[1,2-a]pyrimidine-6-carboxamide (BIO-7488), a potent, selective, and CNS-penetrant IRAK4 inhibitor for the treatment of ischemic stroke","volume":"67","author":"Evans","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0120","doi-asserted-by":"crossref","first-page":"8383","DOI":"10.1021\/acs.jmedchem.4c00560","article-title":"Discovery of BIO-8169 A highly potent, selective, and brain-penetrant IRAK4 inhibitor for the treatment of Neuroinflammation","volume":"67","author":"Pfaffenback","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0125","doi-asserted-by":"crossref","first-page":"10071","DOI":"10.1021\/acs.jmedchem.7b01290","article-title":"Discovery and optimization of Pyrrolopyrimidine inhibitors of Interleukin-1 receptor associated kinase 4 (IRAK4) for the treatment of mutant MyD88L265P diffuse large B-cell lymphoma","volume":"60","author":"Scott","year":"2017","journal-title":"J Med Chem"},{"key":"10.1016\/j.bmc.2025.118333_bb0130","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.bmc.2018.01.008","article-title":"Optimization of permeability in a series of pyrrolotriazine inhibitors of IRAK4","volume":"26","author":"Degorce","year":"2018","journal-title":"Biorg. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0135","doi-asserted-by":"crossref","first-page":"9918","DOI":"10.1021\/acs.jmedchem.9b01346","article-title":"Discovery of a series of 5-Azaquinazolines as orally efficacious IRAK4 inhibitors targeting MyD88L265P mutant diffuse large B cell lymphoma","volume":"62","author":"Degorce","year":"2019","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0140","doi-asserted-by":"crossref","DOI":"10.1016\/j.bmc.2020.115815","article-title":"Improving metabolic stability and removing aldehyde oxidase liability in a 5-asaquinazoline series of IRAK4 inhibitors","volume":"28","author":"Degorce","year":"2020","journal-title":"Biorg. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0145","doi-asserted-by":"crossref","DOI":"10.1016\/j.bmc.2022.116729","article-title":"Identification and optimization of a pyrimidopyridone series of IRAK4 inhibitors","volume":"63","author":"Cumming","year":"2022","journal-title":"Bioorg. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0150","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/j.str.2006.11.001","article-title":"Crystal structures of IRAK-4 kinase in complex with inhibitors: A serine\/threonine kinase with tyrosine as a gatekeeper","volume":"14","author":"Wang","year":"2006","journal-title":"Structure"},{"key":"10.1016\/j.bmc.2025.118333_bb0155","unstructured":"Following our explorations in this area, 1g was reported by Astellas, ref 22."},{"key":"10.1016\/j.bmc.2025.118333_bb0160","doi-asserted-by":"crossref","first-page":"10548","DOI":"10.1021\/acs.jmedchem.3c01823","article-title":"Discovery of KT-413, a targeted protein degrader of IRAK4 and IMiD substrates targeting MYD88 mutant diffuse large B-cell lymphoma","volume":"67","author":"Weiss","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0165","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1021\/acs.jmedchem.3c02184","article-title":"Discovery of clinical candidate AZD5462, a selective Oral allosteric RXFP1 agonist for treatment of heart failure","volume":"67","author":"Granberg","year":"2024","journal-title":"J. Med. Chem."},{"key":"10.1016\/j.bmc.2025.118333_bb0170","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1080\/00498254.2017.1346332","article-title":"In vitro evaluation of the inhibition and induction potential of olaparib, a potent poly(ADP-ribose) polymerase inhibitor, on cytochrome P450","volume":"48","author":"McCormick","year":"2018","journal-title":"Xenobiotica"},{"key":"10.1016\/j.bmc.2025.118333_bb0175","author":"Xiang"}],"container-title":["Bioorganic &amp; Medicinal Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089625002743?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0968089625002743?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:35:22Z","timestamp":1780403722000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0968089625002743"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":35,"alternative-id":["S0968089625002743"],"URL":"https:\/\/doi.org\/10.1016\/j.bmc.2025.118333","relation":{},"ISSN":["0968-0896"],"issn-type":[{"value":"0968-0896","type":"print"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach","name":"articletitle","label":"Article Title"},{"value":"Bioorganic & Medicinal Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.bmc.2025.118333","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.","name":"copyright","label":"Copyright"}],"article-number":"118333"}}