Tatani Kazuya, Hiratochi Masahiro, Nonaka Yoshinori, Isaji Masayuki, Shuto Satoshi
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd. , 4365-1, Kashiwabara, Hotaka, Azumino, Nagano 399-8304, Japan ; Faculty of Pharmaceutical Science and Center for Research and Education on Drug Discovery, Hokkaido University , Kita-12, Nishi-6, Kita-Ku, Sapporo 060-0812, Japan.
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd. , 4365-1, Kashiwabara, Hotaka, Azumino, Nagano 399-8304, Japan.
ACS Med Chem Lett. 2015 Jan 28;6(3):244-8. doi: 10.1021/ml500343r. eCollection 2015 Mar 12.
Purine-rich foods have long been suspected as a major cause of hyperuricemia. We hypothesized that inhibition of human concentrative nucleoside transporter 2 (hCNT2) would suppress increases in serum urate levels derived from dietary purines. To test this hypothesis, the development of potent hCNT2 inhibitors was required. By modifying adenosine, an hCNT2 substrate, we successfully identified 8-aminoadenosine derivatives as a new class of hCNT2 inhibitors. Compound 12 moderately inhibited hCNT2 (IC50 = 52 ± 3.8 μM), and subsequent structure-activity relationship studies led to the discovery of compound 48 (IC50 = 0.64 ± 0.19 μM). Here we describe significant findings about structural requirements of 8-aminoadenosine derivatives for exhibiting potent hCNT2 inhibitory activity.
富含嘌呤的食物长期以来一直被怀疑是高尿酸血症的主要原因。我们推测，抑制人类浓缩核苷转运体2（hCNT2）将抑制饮食中嘌呤导致的血清尿酸水平升高。为了验证这一假设，需要开发有效的hCNT2抑制剂。通过修饰hCNT2底物腺苷，我们成功鉴定出8-氨基腺苷衍生物作为一类新型的hCNT2抑制剂。化合物12对hCNT2有中度抑制作用（IC50 = 52 ± 3.8 μM），随后的构效关系研究导致发现了化合物48（IC50 = 0.64 ± 0.19 μM）。在此，我们描述了关于8-氨基腺苷衍生物表现出强效hCNT2抑制活性的结构要求的重要发现。
