Toward Second‐Generation Cardiomyogenic and Anti‐cardiofibrotic 1,4‐Dihydropyridine‐Class TGFβ Inhibitors

Abstract

Innovative therapeutic modalities for pharmacological intervention of transforming growth factor β (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 maintaining TGFβ‐inhibitory activities. The introduction of a 2‐amino group or 7‐N‐alkyl modification proved to be successful strategies. Aqueous solubility was improved by up to seven‐fold at pH 7.4 and 200‐fold at pH 3 relative to the parent ethyl 4‐(biphenyl‐4‐yl)‐2,7,7‐trimethyl‐5‐oxo‐1,4,5,6,7,8‐hexahydroquinoline‐3‐carboxylate. The therapeutic potential of the presented DHPs was further underscored in view of a potential dual mode of action: The differentiation of committed human iPSC‐derived cardiac progenitor cells (CPCs) was potently stimulated, and the rescue of cardiac fibrosis phenotypes was observed in engineered heart tissue (EHT) constructs.

Higher Carbon Analogues of 1,4‐Dihydropyridines as Potent TGFβ/Smad Inhibitors

“…Additionally, there is one aspect that has already been discovered in our previous studies: a localized, relatively strongly marked negative potential at C8 of the fused ring system . This charge can also be seen on the flat underside of the molecule, as shown in Figure .…”

“…Two typical structural features for 1,4‐DHPs can also be observed: the flattened boat conformation of the annelated ring system, and the pseudo axial position of the substituent at C40, which is thus almost perpendicular to the ring plane . The angle (N2–C40–C41 107°) here is even steeper than the corresponding angle in the biphenyl derivative 1 (118°) . The ethyl ester linked to C29 is also arranged in this plane.…”

“…The biological activity of silicon and germanium DHP was tested in a Smad4‐binding element (SBE4) reporter gene assay in HEK293T as reported previously (Figure ) . For direct comparison, a potent non‐selective ALK4,5,7‐inhibitor (SB‐431542) and the original DHP 1 were tested.…”

“…Representative TGFβ inhibition curves of higher carbon containing 1,4‐DHPs 6a and 6b in comparison to the original DHP 1 and the ALK4,5,7 inhibitor SB‐431542. (Smad 4‐binding element (SBE4) dual luciferase assay in HEK293T cells) , …”

“…Importantly, these compounds inhibit TGFβ signaling via stimulation of proteasomal degradation of the type II TGFβ receptor. Following our initial studies on the structure activity relationships of the identified hit compound 1 (see Figure ),, we substantially explored the structure activity relationships for this unique class of TGFβ inhibitors in a seminal series of reports . Among several SAR‐optimized derivatives, 4′‐( tert ‐butyl) DHP analogue 2 (see Figure ) was highly potent (i.e., IC 50 = 0.28 µ m ).…”