10.1021/jm980288r.s006 Detlef Briel Detlef Briel Dirk Pohlers Dirk Pohlers Mathias Uhlig Mathias Uhlig Silke Vieweg Silke Vieweg Gerhard H. Scholz Gerhard H. Scholz Michael Thormann Michael Thormann Hans-Jörg Hofmann Hans-Jörg Hofmann 3-Amino-5-phenoxythiophenes:  Syntheses and Structure−Function Studies of a Novel Class of Inhibitors of Cellular l-Triiodothyronine Uptake American Chemical Society 1999 concept dicyanoketenedithiolate dose phenolate receptor model show uptake compound prerequisite series thiophene phenoxythiophene benzoyl malodinitrile methylsulfonyl groups inhibition studies HepG 2 hepatoma cells Novel Class orientation transthyretin derivatives show Synthese postulate carbon disulfide Inhibitor Replacement inhibitor binding halogen methanes Uptake cyclization ring systems Cellular Thorpe potency Amino Docking studies 1999-04-30 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/3-Amino-5-phenoxythiophenes_Syntheses_and_Structure_Function_Studies_of_a_Novel_Class_of_Inhibitors_of_Cellular_l-Triiodothyronine_Uptake/3683859 A series of substituted 3-amino-5-phenoxythiophenes was synthesized starting from malodinitrile and carbon disulfide. The resulting dicyanoketenedithiolate reacts via Thorpe−Dieckmann cyclization with halogen methanes bearing electron-withdrawing groups to give thiophene-2-thiolates, which can be transformed into 3-amino-5-(methylsulfonyl)thiophene-4-carbonitriles. Replacement of the methylsulfonyl groups by substituted phenolates provides the substituted 3-amino-5-phenoxythiophenes. Some of the derivatives show a considerable inhibitory potency for the l-T<sub>3</sub> uptake in inhibition studies on human HepG2 hepatoma cells with maximum values of about 60% at a dose of 10<sup>-5</sup> M for the most potent 2-benzoyl derivatives. The structure of the phenoxythiophenes fits well into a general concept derived for other classes of l-T<sub>3</sub> uptake inhibitors, which postulates an angular and perpendicular orientation of the ring systems in these compounds as a prerequisite for an inhibitory potency. Docking studies for the phenoxythiophenes with transthyretin as a receptor model show their preferred attack at the l-T<sub>4</sub>/l-T<sub>3</sub> binding channel.