{"title":"Discovery of orally available 1H-pyrazolo [3, 4-d] pyrimidin-4-amine derivative as a novel BTK inhibitor","authors":"","doi":"10.1016/j.arabjc.2024.105906","DOIUrl":null,"url":null,"abstract":"<div><p>Bruton’s tyrosine kinase (BTK) is a key protein in B cell antigen receptor (BCR) signaling pathway, and is a research hotspot in the clinical treatment of B cell tumors and B cell immune diseases. In this article, based on the structure of Ibrutinib, a series of novel irreversible BTK inhibitors with the scaffolding of <em>1H</em>-pyrazolo [3, 4-<em>d</em>] pyrimidin-4-amine were designed and synthesized. All the compounds showed a moderate to potent inhibitory activity against BTK. Among them, compound <strong>6b</strong> showed the best BTK kinase inhibitory activity with the IC<sub>50</sub> value of 1.2 nM. The ADME/T properties performed by pkCSM demonstrated that compound <strong>6b</strong> possesses a good druglikeness. Further druggability evaluation showed that <strong>6b</strong> exhibited good water solubility and acceptable pharmacokinetic properties. Therefore, compound <strong>6b</strong> provided a promising lead compound for developing novel irreversible BTK inhibitors.</p></div>","PeriodicalId":249,"journal":{"name":"Arabian Journal of Chemistry","volume":null,"pages":null},"PeriodicalIF":5.3000,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1878535224003083/pdfft?md5=2bad4652abc810e1e6972cef74e4d4e7&pid=1-s2.0-S1878535224003083-main.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Arabian Journal of Chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1878535224003083","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Bruton’s tyrosine kinase (BTK) is a key protein in B cell antigen receptor (BCR) signaling pathway, and is a research hotspot in the clinical treatment of B cell tumors and B cell immune diseases. In this article, based on the structure of Ibrutinib, a series of novel irreversible BTK inhibitors with the scaffolding of 1H-pyrazolo [3, 4-d] pyrimidin-4-amine were designed and synthesized. All the compounds showed a moderate to potent inhibitory activity against BTK. Among them, compound 6b showed the best BTK kinase inhibitory activity with the IC50 value of 1.2 nM. The ADME/T properties performed by pkCSM demonstrated that compound 6b possesses a good druglikeness. Further druggability evaluation showed that 6b exhibited good water solubility and acceptable pharmacokinetic properties. Therefore, compound 6b provided a promising lead compound for developing novel irreversible BTK inhibitors.
期刊介绍:
The Arabian Journal of Chemistry is an English language, peer-reviewed scholarly publication in the area of chemistry. The Arabian Journal of Chemistry publishes original papers, reviews and short reports on, but not limited to: inorganic, physical, organic, analytical and biochemistry.
The Arabian Journal of Chemistry is issued by the Arab Union of Chemists and is published by King Saud University together with the Saudi Chemical Society in collaboration with Elsevier and is edited by an international group of eminent researchers.