Synthesis and SAR of b-annulated 1,4-dihydropyridines define cardiomyogenic compounds as novel inhibitors of TGFbeta signaling.

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Schade D, Lanier M, Willems E, Okolotowicz K, Bushway P, Wahlquist C, Gilley C, Mercola M, Cashman JR

Synthesis and SAR of b-annulated 1,4-dihydropyridines define cardiomyogenic compounds as novel inhibitors of TGFbeta signaling.

J Med Chem. 2012 Nov 26;55(22):9946-57. doi: 10.1021/jm301144g. Epub 2012 Nov 6.

PubMed ID

23130626 [ View in PubMed

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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 beta (TGFbeta)/Smad signaling by clearing the type II TGFbeta receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series' structure-activity relationship (SAR) based on TGFbeta inhibition, and evaluated SAR aspects for cell-surface clearance of TGFbeta receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC(50)s for TGFbeta 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 TGFbeta 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
4-(3-Pyridin-2-Yl-1h-Pyrazol-4-Yl)Quinoline	TGF-beta receptor type-1	IC 50 (nM)	40	N/A	N/A	Details