%0 Journal Article
%T Discovery of Novel Chromenopyridine Derivatives as Readthrough-Inducing Drugs.
%A Kawai S
%A Takashima S
%A Ando M
%A Shintaku S
%A Takeda S
%A Otake K
%A Ito Y
%A Fukui M
%A Yamamoto M
%A Shoji Y
%A Shirahase H
%A Kitao T
%J Chem Pharm Bull (Tokyo)
%V 71
%N 12
%D 2023
%M 38044139
%F 1.903
%R 10.1248/cpb.c23-00488
%X Hurler syndrome, a type of Mucopolysaccharidosis type I, is an inherited disorder caused by the accumulation of glycosaminoglycans (GAG) due to a deficiency in lysosomal α-L-iduronidase (IDUA), resulting in multiorgan dysfunction. In many patients with Hurler syndrome, IDUA proteins are not produced due to nonsense mutations in their genes; therefore, readthrough-inducing compounds, such as gentamycin, are expected to restore IDUA proteins by skipping the premature termination codon. In the present study, we synthesized a series of chromenopyridine derivatives to identify novel readthrough-inducing compounds. The readthrough-inducing activities of synthesized compounds were examined by measuring cellular IDUA activities and GAG concentrations in Hurler syndrome patient-derived cells. Compounds with a difluorophenyl group at the 2-position of chromenopyridine, a cyclobutyl group at the 3-position, and a basic side chain or basic fused ring exhibited excellent readthrough-inducing activities. KY-640, a chromenopyridine derivative with a tetrahydroisoquinoline sub-structure, increased the cellular IDUA activities of patient-derived cells by 3.2-fold at 0.3 µM and significantly reduced GAG concentrations, and also significantly increased enzyme activity in mouse models, suggesting its therapeutic potential in patients with Hurler syndrome.