title: Synthesis and SAR of b-annulated 1,4-dihydropyridines define cardiomyogenic compounds as novel inhibitors of TGFβ signaling.
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.
authors.affiliation: Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, California 92121-2804, USA. dennis.schade@tu-dortmund.de
authors.forename: Dennis
authors.initials: D
authors.lastname: Schade
authors.forename: Marion
authors.initials: M
authors.lastname: Lanier
authors.forename: Erik
authors.initials: E
authors.lastname: Willems
authors.forename: Karl
authors.initials: K
authors.lastname: Okolotowicz
authors.forename: Paul
authors.initials: P
authors.lastname: Bushway
authors.forename: Christine
authors.initials: C
authors.lastname: Wahlquist
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gilley
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
authors.forename: John R
authors.initials: JR
authors.lastname: Cashman
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015363:Quinolones / Q000138:chemical synthesis / Q000494:pharmacology*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004095:Dihydropyridines; D015363:Quinolones; D018125:Receptors, Transforming Growth Factor beta; D054852:Small Molecule Libraries; D016212:Transforming Growth Factor beta; C422405:activin A; C577949:ethyl 4-(4-tert-butylphenyl)-2-methyl-5-oxo-7-(n-propyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate; D028341:Activins; C038806:1,4-dihydropyridine; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D002118:Calcium