Toward Optimization of the Second Aryl Substructure Common to Transthyretin Amyloidogenesis Inhibitors Using Biochemical and Structural Studies

摘要

Transthyretin (TTR) amyloidogenesis inhibitors are typically composed of two aromatic rings and a linker. We have previously established optimal structures for one aromatic ring and the linker. Herein, we employ a suboptimal linker and an optimal aryl-X substructure to rank order the desirability of aryl-Z substructures–using a library of 56 N-(3,5-dibromo-4-hydroxyphenyl)benzamides. Co-consideration of amyloid inhibition potency and ex-vivo plasma TTR binding selectivity data reveal that 2,6; 2,5; 2; 3,4,5 and 3,5 aryls bearing small substituents generate the most potent and selective inhibitors, in descending order. These benzamides generally lack undesirable thyroid hormone receptor binding and COX-1 inhibition activity. Three high-resolution TTR•inhibitor crystal structures (1.31-1.35 Å) provide insight into why these inhibitors are potent and selective, enabling future structure-based design of TTR kinetic stabilizers.