Towards second generation cardiomyogenic and anti-cardiofibrotic 1,4-dihydropyridine-class of TGFβ inhibitors.

Innovative therapeutic modalities for pharmacological intervention of TGFβ-dependent diseases are of great value. b-Annelated 1,4-dihydropyridines (DHPs) might be such a class as they induce TGFβ receptor type-II degradation. However, intrinsic drawbacks are associated with this compound class and were systematically addressed in the presented study. It was possible to install polar functionalities and bioisosteric moieties at distinct sites of the molecules while keeping TGFβ inhibiting activities. The introduction of a 2-amino group or 7-N-alkyl modification proved successful strategies. Aqueous solubility was improved up to 7-fold at pH 7.4 and 200 fold at pH 3 compared to the parent ethyl 4-(biphenyl-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate. Therapeutic potential of the presented DHPs was further underlined in view of a potential 'dual mode-of-action": Differentiation of committed human iPSC-derived cardiac progenitor cells (CPCs) was potently stimulated and rescuing of phenotypes of cardiac fibrosis phenotypes was shown in engineered heart tissue (EHT) constructs.