Publications by authors named "Vura B Subrahmanyam"
A series of 2-substituted-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)imidazoles was synthesized and evaluated to optimize a prototype inhibitor of TGF-β type I receptor kinase (ALK5), 6. Combination of replacement of a quinoxalin-6-yl moiety of 6 with a [1,2,4]triazolo[1,5-a]pyridin-6-yl moiety, insertion of a methyleneamino linker, and a o-F substituent in the phenyl ring markedly increased ALK5 inhibitory activity, kinase selectivity, and oral bioavailability. The 12b (EW-7197) inhibited ALK5 with IC50 value of 0.
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- A series of imidazole and pyrazole compounds were synthesized and tested for their ability to inhibit the ALK5 enzyme.
- The most effective compound, pyrazole derivative 21b, demonstrated an IC50 value of 0.018 μM and achieved 95% inhibition in a luciferase reporter assay.
- Docking analysis indicated that 21b fits perfectly into the ATP binding site of ALK5, forming multiple hydrogen bonds, and also showed a high selectivity index against p38α MAP kinase.
A series of 2-benzylamino-4(5)-(6-methylpyridin-2-yl)-5(4)-([1,2,4]triazolo[1,5-a]pyridin-6-yl)thiazoles 12a-ab, 13a, 13b, and 18a-d has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The N-(3-fluorobenzyl)-4-(6-methylpyridin-2-yl)-5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)thiazol-2-amine (12b) inhibited ALK5 phosphorylation with an IC(50) value of 7.01 nM and showed 61% inhibition at 30 nM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct.
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- A range of 1-substituted-3-(6-methylpyridin-2-yl)-4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrazoles has been synthesized and tested for their ability to inhibit the ALK5 enzyme.
- Compound 14n demonstrated strong inhibitory effectiveness with an IC(50) value of 0.57 nM, making it a potent candidate.
- Additionally, it achieved 94% inhibition in a luciferase reporter assay in specific cell lines, indicating high potential for further research and development.
Article Synopsis
- A series of novel compounds, specifically 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)pyrazoles, were synthesized and tested for their ability to inhibit ALK5 activity.
- The compound 2-[3-(6-methylpyridin-2-yl)-4-(quinoxalin-6-yl)-1H-pyrazol-1-yl]-N-phenylethanethioamide (18a) demonstrated a strong inhibitory effect, with an IC(50) value of 0.013 μM.
- Additionally, it achieved 80% inhibition at a concentration of 0.1 μM in
A series of 1-substituted-3(5)-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)pyrazoles 14a-e, 15a-e, 17a-c, and 18a-d have been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. The 6-quinolinyl pyrazole analogue 14b inhibited ALK5 phosphorylation with IC(50) value of 0.022 μM and showed 84% inhibition at 0.
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