Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors.
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.
Johnson
Steven M
SM
Department of Chemistry, The Scripps Research Institute, BCC 265, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Connelly
Stephen
S
Wilson
Ian A
IA
Kelly
Jeffery W
JW
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
D000682:Amyloid; D001583:Benzoxazoles; D016861:Cyclooxygenase Inhibitors; D011228:Prealbumin; D011988:Receptors, Thyroid Hormone; D051545:Cyclooxygenase 1