{Reference Type}: Journal Article
{Title}: Discovery of Novel Chromenopyridine Derivatives as Readthrough-Inducing Drugs.
{Author}: Kawai S;Takashima S;Ando M;Shintaku S;Takeda S;Otake K;Ito Y;Fukui M;Yamamoto M;Shoji Y;Shirahase H;Kitao T;
{Journal}: Chem Pharm Bull (Tokyo)
{Volume}: 71
{Issue}: 12
{Year}: 2023
{Factor}: 1.903
{DOI}: 10.1248/cpb.c23-00488
{Abstract}: 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.