Design, synthesis, and antifibrosis evaluation of 4-(benzo-[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methyl- pyridin-2-yl)pyrazole and 3(5)-(6-methylpyridin- 2-yl)-4-(thieno-[3,2,-c]pyridin-2-yl)pyrazole derivatives. 2019

Wen-Jing Zhu, and Ben-Wen Cui, and Hui Min Wang, and Ji-Xing Nan, and Hu-Ri Piao, and Li-Hua Lian, and Cheng Hua Jin
College of Pharmacy, Yanbian University, Yanji, 133002, PR China.

Six series of 4-(benzo[c][1,2,5]thiadiazol-5-yl)-3(5)-(6-methylpyridin-2-yl)- pyrazoles 18a-d, 19a-d, 22a-d and 3(5)-(6-methylpyridin-2-yl)-4-(thieno[3,2,-c]- pyridin-2-yl)pyrazoles 20a-d, 21a-d, 23c, 23d have been synthesized and evaluated for their activin receptor-like kinase 5 (ALK5) and p38α mitogen activated protein (MAP) kinase inhibitory activities in enzymatic assays. Among these compounds, the most active compound, 22c, inhibited ALK5 phosphorylation with an IC50 value of 0.030 μM in the enzymatic assay. Compound 22c showed four-fold more potent activity against ALK5 kinase than the clinical candidate, compound LY-2157299. The selectivity index of 22c against p38α MAP kinase is 235, which is much higher than that of LY-2157299 (4) and equally selective to that of EW-7197 (218). Compound 22c effectively suppressed protein and mRNA expression of collagen I and α-SMA in TGF-β-induced LX-2 human hepatic stellate cell (HSC), this result shows that compound 22c has the ability to inhibit the activation of HSC. Compound 22c is expected to be a preclinical candidate for the treatment of hepatic fibrosis.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011720 Pyrazoles Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005355 Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Cirrhosis,Fibroses
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000077293 Receptor, Transforming Growth Factor-beta Type I A transmembrane serine-threonine kinase that forms a heteromeric complex with TYPE II TGF-BETA RECEPTORS to bind TGF-BETA and regulate a variety of physiological and pathological processes including CELL CYCLE ARREST; CELL PROLIFERATION; CELL DIFFERENTIATION; WOUND HEALING; EXTRACELLULAR MATRIX production, immunosuppression and ONCOGENESIS. Activin Receptor-like Kinase 5,Receptor, TGF-beta Type I,Serine-Threonine-Protein Kinase Receptor R4,TGF-beta RPK,TGF-beta Receptor Protein Kinase,TGF-beta Type I Receptor,TGF-beta Type I Receptors,TGFBR1,TbetaR-I Kinase,Transforming Growth Factor beta Receptor I,Transforming Growth Factor, beta Receptor 1,Type I TGF-beta Receptor,Type I TGF-beta Receptors,Activin Receptor like Kinase 5,Kinase, TbetaR-I,Serine Threonine Protein Kinase Receptor R4,TGF beta Receptor Protein Kinase,TGF beta Type I Receptor,TGF beta Type I Receptors,TbetaR I Kinase,Type I TGF beta Receptor,Type I TGF beta Receptors
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs

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