2. Academic Validation
  3. Identification of 8-aminoadenosine derivatives as a new class of human concentrative nucleoside transporter 2 inhibitors

Identification of 8-aminoadenosine derivatives as a new class of human concentrative nucleoside transporter 2 inhibitors

  • ACS Med Chem Lett. 2015 Jan 28;6(3):244-8. doi: 10.1021/ml500343r.
Kazuya Tatani 1,  Masahiro Hiratochi 2,  Yoshinori Nonaka 2,  Masayuki Isaji 2,  Satoshi Shuto 3
Affiliations

Affiliations

  • 1 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.
  • 2 Central Research Laboratories, Kissei Pharmaceutical Co., Ltd. , 4365-1, Kashiwabara, Hotaka, Azumino, Nagano 399-8304, Japan.
  • 3 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 ; 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.
PMID: 25815140 DOI: 10.1021/ml500343r
Abstract

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.

Keywords

8-Aminoadenosine derivatives; dietary purines; gout; human concentrative nucleoside transporter 2; hyperuricemia.

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