Toward Second‐Generation Cardiomyogenic and Anti‐cardiofibrotic 1, 4‐Dihydropyridine‐Class TGFβ Inhibitors. (28th February 2019)

• Record Type: Journal Article
• Authors: Längle, Daniel; Werner, Tessa R.; Wesseler, Fabian; Reckzeh, Elena; Schaumann, Niklas; Drowley, Lauren; Polla, Magnus; Plowright, Alleyn T.; Hirt, Marc N.; Eschenhagen, Thomas; Schade, Dennis
• Is Part Of: ChemMedChem. Volume 14:Number 8(2019)
• Page Start: 810
• Page End: 822
• Publication Date: 2019-02-28
• Subjects: 1, 4-dihydropyridines -- cardiac progenitor cells -- engineered heart tissue -- hit-to-lead -- TGFβ receptor; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201900036
• Languages: English
• ISSNs: 1860-7179

Abstract

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. Abstract : Compounds with heart : Our early hit‐to‐lead optimization efforts tackled physicochemical liabilities of unique 1, 4‐dihydropyridine‐type TGFβ signaling inhibitors, i.e., degraders of the TGFβ type II receptor. Efficacy in human cardiac progenitor cells and a cardiac fibrosis model in engineered heart tissue constructs suggest a potential dual mode of action.