ArticleJournal of medicinal chemistry2012
Synthesis and SAR of b-annulated 1,4-dihydropyridines define cardiomyogenic compounds as novel inhibitors of TGFβ signaling.
Article in Journal of medicinal chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 66 citations in OpenAlex.
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- b-Annulated 1,4-dihydropyridines as Notch inhibitors.Bioorganic & medicinal chemistry letters · 2018Article
- Facile Three-Component Synthesis, Insecticidal and Antifungal Evaluation of Novel Dihydropyridine Derivatives.Molecules (Basel, Switzerland) · 2018Article
- Lanthanide and asymmetric catalyzed syntheses of sterically hindered 4-isoxazolyl-1,4-dihydropyridines and 4-isoxazolyl-quinolones.Tetrahedron letters · 2016Article
- 1,5-Disubstituted benzimidazoles that direct cardiomyocyte differentiation from mouse embryonic stem cells.Bioorganic & medicinal chemistry · 2015Article
- High content screening for modulators of cardiac differentiation in human pluripotent stem cells.Methods in molecular biology (Clifton, N.J.) · 2015Article
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Authors and funding
9 authors at 3 institutions in 1 country.
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Abstract
A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a b-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC(50)s for TGFβ inhibition in the nanomolar range (e.g., compound 28, 170 nM). Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (-) enantiomer. This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells.
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