- Pyrazolo[3,4-d]pyrimidine derivatives as irreversible Bruton's tyrosine kinase inhibitors
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4,6-Disubstituted pyrazolo[3,4-d]pyrimidine derivatives were explored as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The structure–activity relationship was established with over 20 derivatives synthesized to determine initial hit compounds, based on activities against BTK enzyme and TMD8 cells. It turns out that introducing 1-acrylamido-4-aminopiperdine (1b) at the C4 position of pyrazolopyrimidine as in 5e, and 3-acrylamido-aniline (1j) as 4-position substituent, such as in 9d, 10d, and 10e, delivered potent in vitro enzyme activities as well as TMD8 cell-based cytotoxicities. Considering kinase selectivity profiles, 5e was selected for in vivo efficacy studies with a murine xenograft model using TMD8 cells, where 5e exhibited moderate tumor growth inhibition activities. Further optimization of 5e and 9d may lead to clinically useful compounds to overcome B-cell-mediated hematologic cancers.
- Achary, Raghavendra,Cho, Sung Yun,Choi, Yunha,Kim, Pilho,Lee, Heung Kyoung,Lee, Joo-Youn,Park, Chi Hoon,Yeom, Hyesu
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supporting information
(2022/02/09)
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- Fused-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient
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The present invention relates to a conjugated pyrimidine derivative, a method for manufacturing the same, and a pharmaceutical composition for preventing or treating Bruton′s tyrosine kinase activity-related diseases containing the same as an active ingredient. The conjugated pyrimidine derivative according to the present invention is excellent in the ability to inhibit the activity of Bruton′s tyrosine kinase or TMD80, and thus can be usefully used for prevention or treatment of diseases related to Bruton′s tyrosine kinase activity, particularly cancer or autoimmune diseases.COPYRIGHT KIPO 2019
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Paragraph 0492; 0493; 0506-0508
(2019/02/02)
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