Arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists covalently bind to the PPARγ ligand binding domain with a unique binding mode
[Display omitted] Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARγ antagonists. The representative...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2022-05, Vol.64, p.128676-128676, Article 128676 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Yoshizawa, Mami Aoyama, Tomomi Itoh, Toshimasa Miyachi, Hiroyuki |
| description | [Display omitted]
Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARγ antagonists. The representative compound, MMT-160, exhibited nanomolar-order PPARγ antagonistic activity. To understand the antagonistic mode of action of MMT-160, mass spectrometric and X-ray crystallographic analysis of MMT-160 in the presence of the PPARγ ligand binding domain (LBD) were performed. The mass spectrometry results clearly indicated that alkynyl amide-type PPARγ antagonists were covalently bound to the PPARγ LBD. The X-ray crystallographic analysis indicated that MMT-160 acted as a Michael acceptor and covalently bound to the PPARγ LBD via Cys285. In addition, MMT-160 bound to the PPARγ LBD with a binding mode that was different from the binding modes observed for PPARγ agonists and partial agonists. |
| doi_str_mv | 10.1016/j.bmcl.2022.128676 |
| format | Article |
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Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARγ antagonists. The representative compound, MMT-160, exhibited nanomolar-order PPARγ antagonistic activity. To understand the antagonistic mode of action of MMT-160, mass spectrometric and X-ray crystallographic analysis of MMT-160 in the presence of the PPARγ ligand binding domain (LBD) were performed. The mass spectrometry results clearly indicated that alkynyl amide-type PPARγ antagonists were covalently bound to the PPARγ LBD. The X-ray crystallographic analysis indicated that MMT-160 acted as a Michael acceptor and covalently bound to the PPARγ LBD via Cys285. In addition, MMT-160 bound to the PPARγ LBD with a binding mode that was different from the binding modes observed for PPARγ agonists and partial agonists.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2022.128676</identifier><identifier>PMID: 35301139</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Alkynyl amide ; Amides - chemistry ; Amides - pharmacology ; Covalent binder ; Cys285 ; Diabetes Mellitus, Type 2 ; Humans ; Ligands ; PPAR gamma - metabolism ; PPARγ ; PPARγantagonist ; Protein Domains</subject><ispartof>Bioorganic & medicinal chemistry letters, 2022-05, Vol.64, p.128676-128676, Article 128676</ispartof><rights>2022 Elsevier Ltd</rights><rights>Copyright © 2022 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-65675b26612c0aa25f44633d3ecd0f5b78d52f978bb5316c70810028c39eb5343</citedby><cites>FETCH-LOGICAL-c400t-65675b26612c0aa25f44633d3ecd0f5b78d52f978bb5316c70810028c39eb5343</cites><orcidid>0000-0002-3764-688X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2022.128676$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35301139$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoshizawa, Mami</creatorcontrib><creatorcontrib>Aoyama, Tomomi</creatorcontrib><creatorcontrib>Itoh, Toshimasa</creatorcontrib><creatorcontrib>Miyachi, Hiroyuki</creatorcontrib><title>Arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists covalently bind to the PPARγ ligand binding domain with a unique binding mode</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARγ antagonists. The representative compound, MMT-160, exhibited nanomolar-order PPARγ antagonistic activity. To understand the antagonistic mode of action of MMT-160, mass spectrometric and X-ray crystallographic analysis of MMT-160 in the presence of the PPARγ ligand binding domain (LBD) were performed. The mass spectrometry results clearly indicated that alkynyl amide-type PPARγ antagonists were covalently bound to the PPARγ LBD. The X-ray crystallographic analysis indicated that MMT-160 acted as a Michael acceptor and covalently bound to the PPARγ LBD via Cys285. In addition, MMT-160 bound to the PPARγ LBD with a binding mode that was different from the binding modes observed for PPARγ agonists and partial agonists.</description><subject>Alkynyl amide</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>Covalent binder</subject><subject>Cys285</subject><subject>Diabetes Mellitus, Type 2</subject><subject>Humans</subject><subject>Ligands</subject><subject>PPAR gamma - metabolism</subject><subject>PPARγ</subject><subject>PPARγantagonist</subject><subject>Protein Domains</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhS0EokPhBVggL8sig__iJBKbUcWfVIkKgcTOcuybqQcnHmzPQF6LvkefCUdTumRl69xzjuz7IfSSkjUlVL7ZrfvR-DUjjK0pa2UjH6EVFVJUXJD6MVqRTpKq7cT3M_QspR0hVBAhnqIzXnNCKe9W6M8mzl77H_M0e6xHZ6HK8x7wHmL47VIYyzUG7waIOodYaZPdUWewOIKBfZHw3S2-uL7efLm7fV0l8LA4AOsp622YXMoJm3DUHqbsZ9y7yeIccL4BfAph77a6iMvETVtsw6jdhH-5fIM1Pkzu5wEehmOw8Bw9GbRP8OL-PEff3r_7evmxuvr84dPl5qoygpBcyVo2dc-kpMwQrVk9CCE5txyMJUPdN62t2dA1bd_XnErTkJYSwlrDOyiK4Ofo4tRbFlDekLIaXTLgvZ4gHJJiUpCu46JbrOxkNTGkFGFQ--hGHWdFiVpYqZ1aWKmFlTqxKqFX9_2HfgT7EPkHpxjengxQfnl0EFUyDiYD1pXlZ2WD-1__X0u9qmU</recordid><startdate>20220515</startdate><enddate>20220515</enddate><creator>Yoshizawa, Mami</creator><creator>Aoyama, Tomomi</creator><creator>Itoh, Toshimasa</creator><creator>Miyachi, Hiroyuki</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><orcidid>https://orcid.org/0000-0002-3764-688X</orcidid></search><sort><creationdate>20220515</creationdate><title>Arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists covalently bind to the PPARγ ligand binding domain with a unique binding mode</title><author>Yoshizawa, Mami ; Aoyama, Tomomi ; Itoh, Toshimasa ; Miyachi, Hiroyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-65675b26612c0aa25f44633d3ecd0f5b78d52f978bb5316c70810028c39eb5343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Alkynyl amide</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Covalent binder</topic><topic>Cys285</topic><topic>Diabetes Mellitus, Type 2</topic><topic>Humans</topic><topic>Ligands</topic><topic>PPAR gamma - metabolism</topic><topic>PPARγ</topic><topic>PPARγantagonist</topic><topic>Protein Domains</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yoshizawa, Mami</creatorcontrib><creatorcontrib>Aoyama, Tomomi</creatorcontrib><creatorcontrib>Itoh, Toshimasa</creatorcontrib><creatorcontrib>Miyachi, Hiroyuki</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 letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yoshizawa, Mami</au><au>Aoyama, Tomomi</au><au>Itoh, Toshimasa</au><au>Miyachi, Hiroyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists covalently bind to the PPARγ ligand binding domain with a unique binding mode</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2022-05-15</date><risdate>2022</risdate><volume>64</volume><spage>128676</spage><epage>128676</epage><pages>128676-128676</pages><artnum>128676</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are drug candidates for the treatment of type 2 diabetes, obesity, and osteoporosis. Previously, we have designed and synthesized a series of substituted phenylalkynyl amide-type PPARγ antagonists. The representative compound, MMT-160, exhibited nanomolar-order PPARγ antagonistic activity. To understand the antagonistic mode of action of MMT-160, mass spectrometric and X-ray crystallographic analysis of MMT-160 in the presence of the PPARγ ligand binding domain (LBD) were performed. The mass spectrometry results clearly indicated that alkynyl amide-type PPARγ antagonists were covalently bound to the PPARγ LBD. The X-ray crystallographic analysis indicated that MMT-160 acted as a Michael acceptor and covalently bound to the PPARγ LBD via Cys285. In addition, MMT-160 bound to the PPARγ LBD with a binding mode that was different from the binding modes observed for PPARγ agonists and partial agonists.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>35301139</pmid><doi>10.1016/j.bmcl.2022.128676</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-3764-688X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alkynyl amide Amides - chemistry Amides - pharmacology Covalent binder Cys285 Diabetes Mellitus, Type 2 Humans Ligands PPAR gamma - metabolism PPARγ PPARγantagonist Protein Domains |
| title | Arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists covalently bind to the PPARγ ligand binding domain with a unique binding mode |
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