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Your search keyword '"Pyrazolo[3,4-d]pyridazinone"' showing total 6 results
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6 results on '"Pyrazolo[3,4-d]pyridazinone"'

1. Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors

Author

Xiaowei Wu, Mengdi Dai, Rongrong Cui, Yulan Wang, Chunpu Li, Xia Peng, Jihui Zhao, Bao Wang, Yang Dai, Dan Feng, Tianbiao Yang, Hualiang Jiang, Meiyu Geng, Jing Ai, Mingyue Zheng, and Hong Liu

Subjects
Tyrosine kinase, Covalent FGFR inhibitors, Virtual screening, Pyrazolo[3,4-d]pyridazinone, Structure−activity relationships, Antitumor efficacy, Therapeutics. Pharmacology, RM1-950
Abstract

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors’ selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.

Published
2021
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2. Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors.

Author

Wu, Xiaowei, Dai, Mengdi, Cui, Rongrong, Wang, Yulan, Li, Chunpu, Peng, Xia, Zhao, Jihui, Wang, Bao, Dai, Yang, Feng, Dan, Yang, Tianbiao, Jiang, Hualiang, Geng, Meiyu, Ai, Jing, Zheng, Mingyue, and Liu, Hong

Subjects
BIOSYNTHESIS, FIBROBLAST growth factor receptors, PYRIDAZINONES, CANCER cell analysis, CANCER cell proliferation
Abstract

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4- d ]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model. A series of pyrazolo[3,4- d ]pyridazinone derivatives were synthesized. Kinase inhibition, cell proliferation, and whole blood stability assays were performed, allowing us to explore structure−activity relationship and to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Compound 10h displayed highly potent antitumor efficacy in the NCI-H1581 xenograft model. [Display omitted] [ABSTRACT FROM AUTHOR]

Published
2021
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3. Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyridazinone derivatives as covalent FGFR inhibitors

Author

Meng-di Dai, Xiaowei Wu, Rongrong Cui, Tianbiao Yang, Xia Peng, Meiyu Geng, Mingyue Zheng, Jihui Zhao, Jing Ai, Yulan Wang, Hualiang Jiang, Chunpu Li, Bao Wang, Hong Liu, Dan Feng, and Yang Dai

Subjects
chemistry.chemical_classification, Virtual screening, 0303 health sciences, Cell growth, lcsh:RM1-950, Biological activity, 03 medical and health sciences, Structure−activity relationships, 0302 clinical medicine, Enzyme, lcsh:Therapeutics. Pharmacology, chemistry, Fibroblast growth factor receptor, Antitumor efficacy, 030220 oncology & carcinogenesis, Immunoblot Analysis, Cancer cell, Cancer research, General Pharmacology, Toxicology and Pharmaceutics, Tyrosine kinase, Covalent FGFR inhibitors, 030304 developmental biology, Whole blood, Pyrazolo[3,4-d]pyridazinone
Abstract

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors’ selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model.

Published
2021

4. Design, synthesis and biological evaluation of pyrazolo[3,4

Author

Xiaowei, Wu, Mengdi, Dai, Rongrong, Cui, Yulan, Wang, Chunpu, Li, Xia, Peng, Jihui, Zhao, Bao, Wang, Yang, Dai, Dan, Feng, Tianbiao, Yang, Hualiang, Jiang, Meiyu, Geng, Jing, Ai, Mingyue, Zheng, and Hong, Liu

Subjects
Virtual screening, SAR, structure−activity relationship, FGFR, fibroblast growth factor receptor, CADD, computer-aided drug design, EGFR, epidermal growth factor receptor, Structure−activity relationships, Antitumor efficacy, RTKs, receptor tyrosine kinases, PLCγ, phospholipase Cγ, GSH, glutathione, PK, pharmacokinetics, Original Article, Tyrosine kinase, Covalent FGFR inhibitors, MAPK, mitogen-activated protein kinase, PI3K, phosphoinositide 3-kinase, Pyrazolo[3,4-d]pyridazinone, BTK, brutons tyrosine kinase
Abstract

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-d]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure−activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors’ selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model., Graphical abstract A series of pyrazolo[3,4-d]pyridazinone derivatives were synthesized. Kinase inhibition, cell proliferation, and whole blood stability assays were performed, allowing us to explore structure−activity relationship and to gain understanding of the structural requirements to modulate covalent inhibitors’ selectivity and reactivity. Compound 10h displayed highly potent antitumor efficacy in the NCI-H1581 xenograft model.Image 1

Published
2020

5. Potential Antileishmanial Activity of 4-N-Acylhydrazone Pyrazolo[3,4-d]pyridazin-7-ones: Synthesis, in vitro Biological Evaluations and Computational Studies

Author

Maria Helena Sarragiotto, Julia Poletto, Gessica M. Ribeiro, Danielle Lazarin Bidóia, Fávero Reisdorfer Paula, Michael J. V. da Silva, Andrey P. Jacomini, Jéssica T.C. Yokoyama, Celso Vataru Nakamura, and Fernanda A. Rosa

Subjects
pyrazolo[3,4-d]pyridazinone, biology, 010405 organic chemistry, Chemistry, Stereochemistry, In silico, N-acylhydrazone, General Chemistry, 010402 general chemistry, biology.organism_classification, 01 natural sciences, In vitro, 0104 chemical sciences, medicine.anatomical_structure, medicine, Selectivity, Axenic, Cytotoxicity, Fibroblast, Amastigote, IC50, Leishmania amazonensis
Abstract

In this work a series of 28 novel pyrazolo[3,4-d]pyridazin-7-ones were synthesized and tested against Leishmania amazonensis (strain WHOM/BR/75/JOSEFA) in promastigote and axenic amastigote forms. Five compounds were active against both cellular forms with IC50 (inhibitory concentration growth of 50%) values of 20.2, 11.7, 16.2, 29.5 and 40.3 µM for promastigote and 17.4, 25.2, 3.84, 21.8 and 22.7 µM for axenic amastigote. All compounds were studied by the Lipinski rule, cytotoxicity both in silico and in vitro to fibroblast line (L929) and macrophages (J774A1), and the most active compound showed a selectivity index of 59.9.

Published
2018

6. Design, synthesis and biological evaluation of pyrazolo[3,4- d ]pyridazinone derivatives as covalent FGFR inhibitors.

Author

Wu X, Dai M, Cui R, Wang Y, Li C, Peng X, Zhao J, Wang B, Dai Y, Feng D, Yang T, Jiang H, Geng M, Ai J, Zheng M, and Liu H

Abstract

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4- d ]pyridazinone derivatives. Kinase inhibition, cell proliferation, and whole blood stability assays were used to evaluate their activity on FGFR, allowing us to explore structure-activity relationships and thus to gain understanding of the structural requirements to modulate covalent inhibitors' selectivity and reactivity. Among them, compound 10h exhibited potent enzymatic activity against FGFR and remarkably inhibited proliferation of various cancer cells associated with FGFR dysregulation, and suppressed FGFR signaling pathway in cancer cells by the immunoblot analysis. Moreover, 10h displayed highly potent antitumor efficacy (TGI = 91.6%, at a dose of 50 mg/kg) in the FGFR1-amplified NCI-H1581 xenograft model., (© 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Published
2021
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