2. Academic Validation
  3. Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor

Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor

  • Bioorg Med Chem. 2020 Apr 1;28(7):115376. doi: 10.1016/j.bmc.2020.115376.
Takafumi Yukawa 1,  Takashi Nakahata 2,  Rei Okamoto 2,  Yuji Ishichi 2,  Yasufumi Miyamoto 2,  Satoshi Nishimura 2,  Tatsuo Oikawa 2,  Kazuki Kubo 2,  Ryutaro Adachi 2,  Yoshinori Satomi 2,  Masanori Nakakariya 2,  Nobuyuki Amano 2,  Masahiro Kamaura 2,  Nobuyuki Matsunaga 2
Affiliations

Affiliations

  • 1 Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: takafumi.yukawa@takeda.com.
  • 2 Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
PMID: 32088125 DOI: 10.1016/j.bmc.2020.115376
Abstract

Sphingomyelin synthase 2 (SMS2) has attracted attention as a drug target for the treatment of various cardiovascular and metabolic diseases. The modification of a high throughput screening hit, 2-quinolone 10, enhanced SMS2 inhibition at nanomolar concentrations with good selectivity against SMS1. To improve the pharmaceutical properties such as passive membrane permeability and aqueous solubility, adjustment of lipophilicity was attempted and 1,8-naphthyridin-2-one 37 was identified as a potent and selective SMS2 inhibitor. A significant reduction in hepatic sphingomyelin levels following repeated treatment in mice suggested that compound 37 could be an effective in vivo tool for clarifying the role of SMS2 Enzyme and developing the treatment for SMS2-related diseases.

Keywords

1,8-naphthyridin-2-one; 2-quinolone; SMS2; Sphingomyelin synthase 2.

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