Synthesis and SAR of b -Annulated 1,4-Dihydropyridines Define Cardiomyogenic Compounds as Novel Inhibitors of TGFβ Signaling

Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, United States.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 11/2012; 55(22). DOI: 10.1021/jm301144g
Source: PubMed


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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    • "Starting off with esters of specific size and branching we could support the hypothesis that particularly C 3 eC 4 containing esters were most potent (i.e., IC 50 ¼ 0.5e0.7 mM), while groups larger than C 4 were detrimental to biological activity. Similar hints were already obtained in our previous study [8]. To address the question whether a simple increase in lipophilicity and/or enrichment in lipid membranes could contribute to potent TGFb inhibition in a cellular assay setup, long chain ethylene glycol (18) and fatty (lauryl) alcohol (13) linker moieties were evaluated but turned out inactive. "
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