Discovery of 1, 8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor. Issue 7 (1st April 2020)

• Record Type: Journal Article
• Authors: Yukawa, Takafumi; Nakahata, Takashi; Okamoto, Rei; Ishichi, Yuji; Miyamoto, Yasufumi; Nishimura, Satoshi; Oikawa, Tatsuo; Kubo, Kazuki; Adachi, Ryutaro; Satomi, Yoshinori; Nakakariya, Masanori; Amano, Nobuyuki; Kamaura, Masahiro; Matsunaga, Nobuyuki
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 7(2020)
• Publication Date: 2020-04-01
• Subjects: Sphingomyelin synthase 2 -- SMS2 -- 2-quinolone -- 1, 8-naphthyridin-2-one; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115376
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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.