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Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties
[Display omitted] The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited...
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Published in: | Bioorganic & medicinal chemistry 2020-12, Vol.28 (24), p.115818-115818, Article 115818 |
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creator | Yamaguchi-Sasaki, Toru Kawaguchi, Takanori Okada, Atsushi Tokura, Seiken Tanaka-Yamamoto, Nozomi Takeuchi, Tomoki Ogata, Yuya Takahashi, Ryo Kurimoto-Tsuruta, Risa Tamaoki, Tomokazu Sugaya, Yutaka Abe-Kumasaka, Tomoko Arikawa, Kaho Yoshida, Ippei Sugiyama, Hiroyuki Kanuma, Kosuke Yoshinaga, Mitsukane |
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The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections. |
doi_str_mv | 10.1016/j.bmc.2020.115818 |
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The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2020.115818</identifier><identifier>PMID: 33190073</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Atropisomer ; Fusion protein ; Macrocycle ; Pyrazolo[1,5-a]pyrimidines ; Respiratory syncytial virus</subject><ispartof>Bioorganic & medicinal chemistry, 2020-12, Vol.28 (24), p.115818-115818, Article 115818</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-790a4f98df262de0fbcbd5b994b5f773933708b688afc544ebd0f3db532625473</citedby><cites>FETCH-LOGICAL-c353t-790a4f98df262de0fbcbd5b994b5f773933708b688afc544ebd0f3db532625473</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33190073$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamaguchi-Sasaki, Toru</creatorcontrib><creatorcontrib>Kawaguchi, Takanori</creatorcontrib><creatorcontrib>Okada, Atsushi</creatorcontrib><creatorcontrib>Tokura, Seiken</creatorcontrib><creatorcontrib>Tanaka-Yamamoto, Nozomi</creatorcontrib><creatorcontrib>Takeuchi, Tomoki</creatorcontrib><creatorcontrib>Ogata, Yuya</creatorcontrib><creatorcontrib>Takahashi, Ryo</creatorcontrib><creatorcontrib>Kurimoto-Tsuruta, Risa</creatorcontrib><creatorcontrib>Tamaoki, Tomokazu</creatorcontrib><creatorcontrib>Sugaya, Yutaka</creatorcontrib><creatorcontrib>Abe-Kumasaka, Tomoko</creatorcontrib><creatorcontrib>Arikawa, Kaho</creatorcontrib><creatorcontrib>Yoshida, Ippei</creatorcontrib><creatorcontrib>Sugiyama, Hiroyuki</creatorcontrib><creatorcontrib>Kanuma, Kosuke</creatorcontrib><creatorcontrib>Yoshinaga, Mitsukane</creatorcontrib><title>Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.</description><subject>Atropisomer</subject><subject>Fusion protein</subject><subject>Macrocycle</subject><subject>Pyrazolo[1,5-a]pyrimidines</subject><subject>Respiratory syncytial virus</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kUtv1DAUhS1ERaeFH8AGeckmgx3nZbFCbaFIldjA2vLjmvEoiYMfg_KT-i_raFqWrK6s-51zbB-E3lOyp4R2n457Nel9Tepypu1Ah1doR5uuqRjj9DXaEd4NFRl4d4muYjwSQuqG0zfokjHKCenZDj3euqj9CcKKvcUSLz7BnLDJcsRuPjjlkg_b6q8bTZXWBbCcDZ5ykgULEBcXZEFWHNdZr8kV3cmFHLHN0fkZL6E4ujnidAg-_z6UCXjyJo8ybfstNQW_uOgnCCUzQdB-Ljd6kS8QkoP4Fl1YOUZ49zyv0a-vdz9v7quHH9--33x5qDRrWap6TmRj-WBs3dUGiFVamVZx3qjW9j3jjPVkUN0wSKvbpgFliGVGtazwbdOza_Tx7Fui_2SISUzli2Ac5Qw-R1E3HSWEtrwrKD2jOvgYA1ixBDfJsApKxNaQOIrSkNgaEueGiubDs31WE5h_ipdKCvD5DEB55MlBEFE7mDUYF0AnYbz7j_0Ts6mm4g</recordid><startdate>20201215</startdate><enddate>20201215</enddate><creator>Yamaguchi-Sasaki, Toru</creator><creator>Kawaguchi, Takanori</creator><creator>Okada, Atsushi</creator><creator>Tokura, Seiken</creator><creator>Tanaka-Yamamoto, Nozomi</creator><creator>Takeuchi, Tomoki</creator><creator>Ogata, Yuya</creator><creator>Takahashi, Ryo</creator><creator>Kurimoto-Tsuruta, Risa</creator><creator>Tamaoki, Tomokazu</creator><creator>Sugaya, Yutaka</creator><creator>Abe-Kumasaka, Tomoko</creator><creator>Arikawa, Kaho</creator><creator>Yoshida, Ippei</creator><creator>Sugiyama, Hiroyuki</creator><creator>Kanuma, Kosuke</creator><creator>Yoshinaga, Mitsukane</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20201215</creationdate><title>Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties</title><author>Yamaguchi-Sasaki, Toru ; Kawaguchi, Takanori ; Okada, Atsushi ; Tokura, Seiken ; Tanaka-Yamamoto, Nozomi ; Takeuchi, Tomoki ; Ogata, Yuya ; Takahashi, Ryo ; Kurimoto-Tsuruta, Risa ; Tamaoki, Tomokazu ; Sugaya, Yutaka ; Abe-Kumasaka, Tomoko ; Arikawa, Kaho ; Yoshida, Ippei ; Sugiyama, Hiroyuki ; Kanuma, Kosuke ; Yoshinaga, Mitsukane</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-790a4f98df262de0fbcbd5b994b5f773933708b688afc544ebd0f3db532625473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Atropisomer</topic><topic>Fusion protein</topic><topic>Macrocycle</topic><topic>Pyrazolo[1,5-a]pyrimidines</topic><topic>Respiratory syncytial virus</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamaguchi-Sasaki, Toru</creatorcontrib><creatorcontrib>Kawaguchi, Takanori</creatorcontrib><creatorcontrib>Okada, Atsushi</creatorcontrib><creatorcontrib>Tokura, Seiken</creatorcontrib><creatorcontrib>Tanaka-Yamamoto, Nozomi</creatorcontrib><creatorcontrib>Takeuchi, Tomoki</creatorcontrib><creatorcontrib>Ogata, Yuya</creatorcontrib><creatorcontrib>Takahashi, Ryo</creatorcontrib><creatorcontrib>Kurimoto-Tsuruta, Risa</creatorcontrib><creatorcontrib>Tamaoki, Tomokazu</creatorcontrib><creatorcontrib>Sugaya, Yutaka</creatorcontrib><creatorcontrib>Abe-Kumasaka, Tomoko</creatorcontrib><creatorcontrib>Arikawa, Kaho</creatorcontrib><creatorcontrib>Yoshida, Ippei</creatorcontrib><creatorcontrib>Sugiyama, Hiroyuki</creatorcontrib><creatorcontrib>Kanuma, Kosuke</creatorcontrib><creatorcontrib>Yoshinaga, Mitsukane</creatorcontrib><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>Yamaguchi-Sasaki, Toru</au><au>Kawaguchi, Takanori</au><au>Okada, Atsushi</au><au>Tokura, Seiken</au><au>Tanaka-Yamamoto, Nozomi</au><au>Takeuchi, Tomoki</au><au>Ogata, Yuya</au><au>Takahashi, Ryo</au><au>Kurimoto-Tsuruta, Risa</au><au>Tamaoki, Tomokazu</au><au>Sugaya, Yutaka</au><au>Abe-Kumasaka, Tomoko</au><au>Arikawa, Kaho</au><au>Yoshida, Ippei</au><au>Sugiyama, Hiroyuki</au><au>Kanuma, Kosuke</au><au>Yoshinaga, Mitsukane</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2020-12-15</date><risdate>2020</risdate><volume>28</volume><issue>24</issue><spage>115818</spage><epage>115818</epage><pages>115818-115818</pages><artnum>115818</artnum><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>33190073</pmid><doi>10.1016/j.bmc.2020.115818</doi><tpages>1</tpages></addata></record> |
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subjects | Atropisomer Fusion protein Macrocycle Pyrazolo[1,5-a]pyrimidines Respiratory syncytial virus |
title | Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties |
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