title: Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors.
abstract: To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also display high binding selectivity in blood, it proves useful to systematically optimize each of the three substructural elements that comprise a typical inhibitor: the two aryl rings and the linker joining them. In the first study, described herein, structural modifications to one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several potent and highly selective amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding. High resolution crystal structures (1.3-1.5 A) of three inhibitors (2f, 4f, and 4d) in complex with TTR were obtained to characterize their binding orientation. Collectively, the results demonstrate that thyroid hormone-like substitution patterns on one aryl ring lead to potent and highly selective TTR amyloidogenesis inhibitors that lack undesirable thyroid hormone receptor or COX-1 binding.
authors: Department of Chemistry, The Scripps Research Institute, BCC 265, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors: Steven M
authors: SM
authors: Johnson
authors: Stephen
authors: S
authors: Connelly
authors: Ian A
authors: IA
authors: Wilson
authors: Jeffery W
authors: JW
authors: Kelly
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000097:blood / Q000737:chemistry; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1 / Q000737:chemistry; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008958:Models, Molecular; D011228:Prealbumin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000682:Amyloid; D001583:Benzoxazoles; D016861:Cyclooxygenase Inhibitors; D011228:Prealbumin; D011988:Receptors, Thyroid Hormone; D051545:Cyclooxygenase 1