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Synthesis and biological evaluation of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives as novel, potent of ALK5 receptor inhibitors.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2022 Apr 01; Vol. 61, pp. 128552. Date of Electronic Publication: 2022 Jan 18. - Publication Year :
- 2022
-
Abstract
- The transforming growth factor type β receptor I (TGF-β R1, also known as activin-like kinase 5 or ALK5) plays a significant role in the pathogenesis of multiple diseases such as malignant tumors and tissue fibrosis. Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. Herein, a novel series of 4-(pyridine-4-oxy)-3-(tetrahydro-2H-pyran-4-yl)-pyrazole derivatives was synthesized and identified as ALK5 inhibitors. Among them, compound 8h inhibited ALK5 autophosphorylation and NIH3T3 cell activity with IC <subscript>50</subscript> values of 25 nM and 74.6 nM, respectively. Compound 8h also showed favorable pharmacokinetic profile and ameliorated hERG inhibition. More importantly, 30 mg/kg oral administration of 8h could significantly induce tumour growth inhibition in CT26 xenograft model without obvious toxicity.<br /> (Copyright © 2022 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Mice
Molecular Structure
NIH 3T3 Cells
Neoplasms, Experimental drug therapy
Neoplasms, Experimental metabolism
Neoplasms, Experimental pathology
Protein Kinase Inhibitors chemical synthesis
Protein Kinase Inhibitors chemistry
Pyrazoles chemical synthesis
Pyrazoles chemistry
Pyridines chemical synthesis
Pyridines chemistry
Receptor, Transforming Growth Factor-beta Type I metabolism
Structure-Activity Relationship
Antineoplastic Agents pharmacology
Protein Kinase Inhibitors pharmacology
Pyrazoles pharmacology
Pyridines pharmacology
Receptor, Transforming Growth Factor-beta Type I antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 61
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 35051574
- Full Text :
- https://doi.org/10.1016/j.bmcl.2022.128552