Design, synthesis and biological evaluation of novel 3-substituted pyrazolopyrimidine derivatives as potent Bruton’s tyrosine kinase (BTK) inhibitors

Zheng, Nan; Pan, Jing; Hao, Qun; Li, Yingxia; Zhou, Weicheng

doi:10.1016/j.bmc.2018.03.017

Cited by 22 publications

(13 citation statements)

References 24 publications

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“…11, with the phenyl linked to the core by an alkynyl ether, showed high potency against BTK comparable to 3, with an IC 50 value of 7.95 nM, whilst demonstrating a better physicochemical profile than the approved drug. 51 11 was further optimised through the design and synthesis of 15 molecules containing alterations to the warhead in the N1-position. One of the derivatives synthesised, vinyl sulphonamide 12, demonstrated an improved BTK IC 50 than 3 at 4.2 nM.…”

Section: Btkmentioning

confidence: 99%

“…Further multi-kinase inhibitors for VEGFR have also been approved and developed for the treatment of cancer, including sunitinib, pazopanib, vandetanib and cabozantinib (20). 135 Pyrazolo [3,4-d]pyrimidines have been designed to inhibit this VEGFR2, based on the different binding modes of sorafenib (51) and linifanib, which binds to the ATP pocket…”

Section: Vegfrmentioning

confidence: 99%

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Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

Baillache

Unciti‐Broceta

2020

RSC Med. Chem.

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Section: Btkmentioning

confidence: 99%

Section: Vegfrmentioning

confidence: 99%

Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

Baillache

Unciti‐Broceta

2020

RSC Med. Chem.

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“…The reaction unfolds in this manner given the presence of electrophilic groups at C4 prone to suffer nucleophilic substitution by the second reagent whenever the latter possesses a sufficiently nucleophilic moiety to promote the condensation, besides the electrophilic one attacked by the exocyclic amine from 5-aminopyrazole. Pyrazolo [1,5-a]pyrimidines belong to a class of compounds of noteworthy interest for organic and medicinal chemists [17,31,[123][124][125][126][127]. As the name suggests, this chemotype results from fusion of two heterocyclic systems: the pyrazole ring and the pyrimidine ring.…”

Section: Intramolecular Cyclization Of 3(5)-aminopyrazolementioning

confidence: 99%

Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles

2019

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Pyrazoles are known as versatile scaffolds in organic synthesis and medicinal chemistry, often used as starting materials for the preparation of more complex heterocyclic systems with relevance in the pharmaceutical field. Pyrazoles are also interesting compounds from a structural viewpoint, mainly because they exhibit tautomerism. This phenomenon may influence their reactivity, with possible impact on the synthetic strategies where pyrazoles take part, as well as on the biological activities of targets bearing a pyrazole moiety, since a change in structure translates into changes in properties. Investigations of the structure of pyrazoles that unravel the tautomeric and conformational preferences are therefore of upmost relevance. 3(5)-Aminopyrazoles are largely explored as precursors in the synthesis of condensed heterocyclic systems, namely pyrazolo[1,5-a]pyrimidines. However, the information available in the literature concerning the structure and chemistry of 3(5)-aminopyrazoles is scarce and disperse. We provide a revision of data on the present subject, based on investigations using theoretical and experimental methods, together with the applications of the compounds in synthesis. It is expected that the combined information will contribute to a deeper understanding of structure/reactivity relationships in this class of heterocycles, with a positive impact in the design of synthetic methods, where they take part.

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“…Among them, compound 14 ( Figure 7 ) exhibited excellent potency (IC 50 = 7.95 nM against BTK enzymes, 8.91 μM against Ramos cells, and 1.80 μM against Raji cells), with better hydrophilicity (ClogP = 3.33). These investigations provided new information to discover C-3-substituted pyrazolo-pyrimidine derivatives as novel anticancer agents [ 85 ].…”

Section: Recent Advances In Btkismentioning

confidence: 99%

The Development of BTK Inhibitors: A Five-Year Update

et al. 2021

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Bruton’s tyrosine kinase (BTK) represented, in the past ten years, an important target for the development of new therapeutic agents that could be useful for cancer and autoimmune disorders. To date, five compounds, able to block BTK in an irreversible manner, have been launched in the market, whereas many reversible BTK inhibitors (BTKIs), with reduced side effects that are more useful for long-term administration in autoimmune disorders, are under clinical investigation. Despite the presence in the literature of many articles and reviews, studies on BTK function and BTKIs are of great interest for pharmaceutical companies as well as academia. This review is focused on compounds that have appeared in the literature from 2017 that are able to block BTK in an irreversible or reversible manner; also, new promising tunable irreversible inhibitors, as well as PROTAC molecules, have been reported. This summary could improve the knowledge of the chemical diversity of BTKIs and provide information for future studies, particularly from the medicinal chemistry point of view. Data reported here are collected from different databases (Scifinder, Web of Science, Scopus, Google Scholar, and Pubmed) using “BTK” and “BTK inhibitors” as keywords.

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Design, synthesis and biological evaluation of novel 3-substituted pyrazolopyrimidine derivatives as potent Bruton’s tyrosine kinase (BTK) inhibitors

Cited by 22 publications

References 24 publications

Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

Revisiting the Structure and Chemistry of 3(5)-Substituted Pyrazoles

The Development of BTK Inhibitors: A Five-Year Update

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