Systemic optimization and structural evaluation of quinoline derivatives as transthyretin amyloidogenesis inhibitors.

Wild type transthyretin (TTR) and mutant TTR misfold and misassemble into a variety of extracellular insoluble amyloid fibril and/or amorphous aggregate, which are associated with a variety of human amyloid diseases. To develop potent TTR amyloidogenesis inhibitors, we have designed and synthesized a focused library of quinoline derivatives by Pd-catalyzed coupling reaction and by the Horner-Wadsworth-Emmons reaction. The resulting 2-alkynylquinoline derivatives, (E)-2-alkenylquinoline derivatives, and (E)-3-alkenylquinoline derivatives were evaluated to inhibit TTR amyloidogenesis by utilizing the acid-mediated TTR fibril formation. Among these quinoline derivatives, compound 14c exhibited the most potent anti-TTR fibril formation activity in the screening studies, with IC50 values of 1.49 μM against WT-TTR and 1.63 μM against more amyloidogenic V30 M TTR mutant. That is comparable to that of approved therapeutic drug, tafamidis, to ameliorate transthyretin-related amyloidosis. Furthermore, rationalization of the increased efficacy of compound 14c bearing a hydrophobic substituent, such as chloride, was carried out by utilizing in silico docking study that could focus on the region of the thyroid hormone thyroxine (T4) binding sites. Additionally, the most potent compound 14c exhibited good pharmacokinetics properties. Taken together, the novel quinoline derivatives could potentially be explored as potential drug candidates to treat the human TTR amyloidosis.