Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor
[Display omitted] 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 selectivi...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2020-04, Vol.28 (7), p.115376-115376, Article 115376 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | 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 |
| description | [Display omitted]
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. |
| doi_str_mv | 10.1016/j.bmc.2020.115376 |
| format | Article |
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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.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2020.115376</identifier><identifier>PMID: 32088125</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>1,8-naphthyridin-2-one ; 2-quinolone ; Animals ; Cell Line ; Drug Discovery ; Enzyme Inhibitors ; Humans ; Male ; Mice ; SMS2 ; Sphingomyelin synthase 2 ; Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors</subject><ispartof>Bioorganic & medicinal chemistry, 2020-04, Vol.28 (7), p.115376-115376, Article 115376</ispartof><rights>2020 Elsevier Ltd</rights><rights>Copyright © 2020 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-7a0afa4a021b50a81476d58cc4b5ad736a4707661e776aab53e4ad640340d8d53</citedby><cites>FETCH-LOGICAL-c353t-7a0afa4a021b50a81476d58cc4b5ad736a4707661e776aab53e4ad640340d8d53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2020.115376$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32088125$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yukawa, Takafumi</creatorcontrib><creatorcontrib>Nakahata, Takashi</creatorcontrib><creatorcontrib>Okamoto, Rei</creatorcontrib><creatorcontrib>Ishichi, Yuji</creatorcontrib><creatorcontrib>Miyamoto, Yasufumi</creatorcontrib><creatorcontrib>Nishimura, Satoshi</creatorcontrib><creatorcontrib>Oikawa, Tatsuo</creatorcontrib><creatorcontrib>Kubo, Kazuki</creatorcontrib><creatorcontrib>Adachi, Ryutaro</creatorcontrib><creatorcontrib>Satomi, Yoshinori</creatorcontrib><creatorcontrib>Nakakariya, Masanori</creatorcontrib><creatorcontrib>Amano, Nobuyuki</creatorcontrib><creatorcontrib>Kamaura, Masahiro</creatorcontrib><creatorcontrib>Matsunaga, Nobuyuki</creatorcontrib><title>Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
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.</description><subject>1,8-naphthyridin-2-one</subject><subject>2-quinolone</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Drug Discovery</subject><subject>Enzyme Inhibitors</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>SMS2</subject><subject>Sphingomyelin synthase 2</subject><subject>Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi0EokvhB3BBPnIgW38nK06o5aNSJS7lbE3sWeIlsYOdXSn_vi5bOHIajeaZV3ofQt5ytuWMm6vDtp_cVjBRd65la56RDVdGNVLu-HOyYTvTNazbmQvyqpQDY0yoHX9JLqRgXceF3pBfN6G4dMK80rSn_EPXRJiHZVhz8CE2okkRqcccTrCEE1IoFOicFowLhehpwRHdn0uZhxB_pmnFMURa1rgMUJAKGuIQ-rCk_Jq82MNY8M3TvCQ_vny-v_7W3H3_env96a5xUsulaYHBHhQwwXvNoOOqNV53zqleg2-lAdWy1hiObWsAei1RgTeKScV857W8JO_PuXNOv49YFjvVkjiOEDEdixXSyNpfc1ZRfkZdTqVk3Ns5hwnyajmzj47twVbH9tGxPTuuP--e4o_9hP7fx1-pFfh4BrCWPAXMtriA0aEPucqyPoX_xD8AioSMZA</recordid><startdate>20200401</startdate><enddate>20200401</enddate><creator>Yukawa, Takafumi</creator><creator>Nakahata, Takashi</creator><creator>Okamoto, Rei</creator><creator>Ishichi, Yuji</creator><creator>Miyamoto, Yasufumi</creator><creator>Nishimura, Satoshi</creator><creator>Oikawa, Tatsuo</creator><creator>Kubo, Kazuki</creator><creator>Adachi, Ryutaro</creator><creator>Satomi, Yoshinori</creator><creator>Nakakariya, Masanori</creator><creator>Amano, Nobuyuki</creator><creator>Kamaura, Masahiro</creator><creator>Matsunaga, Nobuyuki</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20200401</creationdate><title>Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-7a0afa4a021b50a81476d58cc4b5ad736a4707661e776aab53e4ad640340d8d53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>1,8-naphthyridin-2-one</topic><topic>2-quinolone</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Drug Discovery</topic><topic>Enzyme Inhibitors</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>SMS2</topic><topic>Sphingomyelin synthase 2</topic><topic>Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yukawa, Takafumi</creatorcontrib><creatorcontrib>Nakahata, Takashi</creatorcontrib><creatorcontrib>Okamoto, Rei</creatorcontrib><creatorcontrib>Ishichi, Yuji</creatorcontrib><creatorcontrib>Miyamoto, Yasufumi</creatorcontrib><creatorcontrib>Nishimura, Satoshi</creatorcontrib><creatorcontrib>Oikawa, Tatsuo</creatorcontrib><creatorcontrib>Kubo, Kazuki</creatorcontrib><creatorcontrib>Adachi, Ryutaro</creatorcontrib><creatorcontrib>Satomi, Yoshinori</creatorcontrib><creatorcontrib>Nakakariya, Masanori</creatorcontrib><creatorcontrib>Amano, Nobuyuki</creatorcontrib><creatorcontrib>Kamaura, Masahiro</creatorcontrib><creatorcontrib>Matsunaga, Nobuyuki</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yukawa, Takafumi</au><au>Nakahata, Takashi</au><au>Okamoto, Rei</au><au>Ishichi, Yuji</au><au>Miyamoto, Yasufumi</au><au>Nishimura, Satoshi</au><au>Oikawa, Tatsuo</au><au>Kubo, Kazuki</au><au>Adachi, Ryutaro</au><au>Satomi, Yoshinori</au><au>Nakakariya, Masanori</au><au>Amano, Nobuyuki</au><au>Kamaura, Masahiro</au><au>Matsunaga, Nobuyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>28</volume><issue>7</issue><spage>115376</spage><epage>115376</epage><pages>115376-115376</pages><artnum>115376</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
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.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>32088125</pmid><doi>10.1016/j.bmc.2020.115376</doi><tpages>1</tpages></addata></record> |
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| subjects | 1,8-naphthyridin-2-one 2-quinolone Animals Cell Line Drug Discovery Enzyme Inhibitors Humans Male Mice SMS2 Sphingomyelin synthase 2 Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors |
| title | Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor |
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