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

TY - JOUR

T1 - Toward Second-Generation Cardiomyogenic and Anti-cardiofibrotic 1,4-Dihydropyridine-Class TGFβ Inhibitors

AU - Längle, Daniel

AU - Werner, Tessa R

AU - Wesseler, Fabian

AU - Reckzeh, Elena

AU - Schaumann, Niklas

AU - Drowley, Lauren

AU - Polla, Magnus

AU - Plowright, Alleyn T

AU - Hirt, Marc N

AU - Eschenhagen, Thomas

AU - Schade, Dennis

N1 - © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2019/4/17

Y1 - 2019/4/17

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation/drug effects

KW - Dihydropyridines/chemical synthesis

KW - Drug Design

KW - Humans

KW - Induced Pluripotent Stem Cells/cytology

KW - Myocardial Infarction/therapy

KW - Myocytes, Cardiac/cytology

KW - Rats

KW - Receptors, Transforming Growth Factor beta/metabolism

KW - Smad Proteins/antagonists & inhibitors

KW - Solubility

KW - Structure-Activity Relationship

KW - Tissue Engineering

KW - Tissue Scaffolds/chemistry

KW - Transforming Growth Factor beta/antagonists & inhibitors

U2 - 10.1002/cmdc.201900036

DO - 10.1002/cmdc.201900036

M3 - SCORING: Journal article

C2 - 30768867

VL - 14

SP - 810

EP - 822

JO - CHEMMEDCHEM

JF - CHEMMEDCHEM

SN - 1860-7179

IS - 8

ER -