5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors
A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzym...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2012-12, Vol.20 (24), p.7128-7138 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Amada, Hideaki Sekiguchi, Yoshinori Ono, Naoya Koami, Takeshi Takayama, Tetsuo Yabuuchi, Tetsuya Katakai, Hironori Ikeda, Akiko Aoki, Mari Naruse, Takumi Wada, Reiko Nozoe, Akiko Sato, Masakazu |
| description | A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50=5.5nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=36nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals). |
| doi_str_mv | 10.1016/j.bmc.2012.09.066 |
| format | Article |
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These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50=5.5nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=36nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2012.09.066</identifier><identifier>PMID: 23117174</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>ALK5 inhibitor ; Alopecia ; Animals ; Biological and medical sciences ; Female ; Imidazoles - pharmacology ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pharmacology. Drug treatments ; Protein-Serine-Threonine Kinases - antagonists & inhibitors ; Protein-Serine-Threonine Kinases - chemistry ; Receptors, Transforming Growth Factor beta - antagonists & inhibitors ; Receptors, Transforming Growth Factor beta - chemistry ; Solubility ; Topical application ; Transforming growth factor-β</subject><ispartof>Bioorganic & medicinal chemistry, 2012-12, Vol.20 (24), p.7128-7138</ispartof><rights>2012 Elsevier Ltd</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2012 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c383t-33dd34422e489699cdacb389e955ab9653c9ffb01bf14051343402ad99f6da343</citedby><cites>FETCH-LOGICAL-c383t-33dd34422e489699cdacb389e955ab9653c9ffb01bf14051343402ad99f6da343</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089612008000$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26727245$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23117174$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Amada, Hideaki</creatorcontrib><creatorcontrib>Sekiguchi, Yoshinori</creatorcontrib><creatorcontrib>Ono, Naoya</creatorcontrib><creatorcontrib>Koami, Takeshi</creatorcontrib><creatorcontrib>Takayama, Tetsuo</creatorcontrib><creatorcontrib>Yabuuchi, Tetsuya</creatorcontrib><creatorcontrib>Katakai, Hironori</creatorcontrib><creatorcontrib>Ikeda, Akiko</creatorcontrib><creatorcontrib>Aoki, Mari</creatorcontrib><creatorcontrib>Naruse, Takumi</creatorcontrib><creatorcontrib>Wada, Reiko</creatorcontrib><creatorcontrib>Nozoe, Akiko</creatorcontrib><creatorcontrib>Sato, Masakazu</creatorcontrib><title>5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50=5.5nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=36nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).</description><subject>ALK5 inhibitor</subject><subject>Alopecia</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Female</subject><subject>Imidazoles - pharmacology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein-Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Protein-Serine-Threonine Kinases - chemistry</subject><subject>Receptors, Transforming Growth Factor beta - antagonists & inhibitors</subject><subject>Receptors, Transforming Growth Factor beta - chemistry</subject><subject>Solubility</subject><subject>Topical application</subject><subject>Transforming growth factor-β</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUuOEzEQhi0EYkLgAGyQN0hBwo1f7cRiBSNgRhqJDawtt109cdQvbCcocxuuwEE4E26SgR0r2_V_VeWqH6HnjFaMMvVmVzW9qzhlvKK6oko9QAsmlSRCaPYQLahWG0I3Wl2gJyntKKVcavYYXXDB2Jqt5QL9qMmKvRbkPQx3Y94Gezd2RJFj94pIspKkh7w9dmRG7lX-R2VXJPTBzxHAHmI42BwOkLBNeBozDBnbweMEHbhZwDnaIbVj7MNwi2_j-D1vcWtdHiP59RPn4wT4GkdwMJUQDsM2NKHc0lP0qLVdgmfnc4m-fvzw5fKK3Hz-dH357oY4sRG5jOy9kJJzkGVgrZ23rhEbDbqubaNVLZxu24aypmWS1kxIISm3XutWeVteS7Q61Z3i-G0PKZs-JAddZwcY98kwzqlQkpVuS8ROqItjShFaM8XQ23g0jJrZGbMzxRkzO2OoNsWZkvPiXH7f9OD_ZtxbUYCXZ8AmZ7u2rMuF9I9Ta77msi7c2xMHZRmHANEkF2Bw4EPZXjZ-DP_5xm-ARquv</recordid><startdate>20121215</startdate><enddate>20121215</enddate><creator>Amada, Hideaki</creator><creator>Sekiguchi, Yoshinori</creator><creator>Ono, Naoya</creator><creator>Koami, Takeshi</creator><creator>Takayama, Tetsuo</creator><creator>Yabuuchi, Tetsuya</creator><creator>Katakai, Hironori</creator><creator>Ikeda, Akiko</creator><creator>Aoki, Mari</creator><creator>Naruse, Takumi</creator><creator>Wada, Reiko</creator><creator>Nozoe, Akiko</creator><creator>Sato, Masakazu</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>IQODW</scope><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>20121215</creationdate><title>5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors</title><author>Amada, Hideaki ; Sekiguchi, Yoshinori ; Ono, Naoya ; Koami, Takeshi ; Takayama, Tetsuo ; Yabuuchi, Tetsuya ; Katakai, Hironori ; Ikeda, Akiko ; Aoki, Mari ; Naruse, Takumi ; Wada, Reiko ; Nozoe, Akiko ; Sato, Masakazu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-33dd34422e489699cdacb389e955ab9653c9ffb01bf14051343402ad99f6da343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>ALK5 inhibitor</topic><topic>Alopecia</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Female</topic><topic>Imidazoles - pharmacology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein-Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Protein-Serine-Threonine Kinases - chemistry</topic><topic>Receptors, Transforming Growth Factor beta - antagonists & inhibitors</topic><topic>Receptors, Transforming Growth Factor beta - chemistry</topic><topic>Solubility</topic><topic>Topical application</topic><topic>Transforming growth factor-β</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Amada, Hideaki</creatorcontrib><creatorcontrib>Sekiguchi, Yoshinori</creatorcontrib><creatorcontrib>Ono, Naoya</creatorcontrib><creatorcontrib>Koami, Takeshi</creatorcontrib><creatorcontrib>Takayama, Tetsuo</creatorcontrib><creatorcontrib>Yabuuchi, Tetsuya</creatorcontrib><creatorcontrib>Katakai, Hironori</creatorcontrib><creatorcontrib>Ikeda, Akiko</creatorcontrib><creatorcontrib>Aoki, Mari</creatorcontrib><creatorcontrib>Naruse, Takumi</creatorcontrib><creatorcontrib>Wada, Reiko</creatorcontrib><creatorcontrib>Nozoe, Akiko</creatorcontrib><creatorcontrib>Sato, Masakazu</creatorcontrib><collection>Pascal-Francis</collection><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>Amada, Hideaki</au><au>Sekiguchi, Yoshinori</au><au>Ono, Naoya</au><au>Koami, Takeshi</au><au>Takayama, Tetsuo</au><au>Yabuuchi, Tetsuya</au><au>Katakai, Hironori</au><au>Ikeda, Akiko</au><au>Aoki, Mari</au><au>Naruse, Takumi</au><au>Wada, Reiko</au><au>Nozoe, Akiko</au><au>Sato, Masakazu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2012-12-15</date><risdate>2012</risdate><volume>20</volume><issue>24</issue><spage>7128</spage><epage>7138</epage><pages>7128-7138</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-β-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50=5.5nM) as well as inhibitory activity against TGF-β-induced Smad2/3 phosphorylation at a cellular level (IC50=36nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals).</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>23117174</pmid><doi>10.1016/j.bmc.2012.09.066</doi><tpages>11</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry, 2012-12, Vol.20 (24), p.7128-7138 |
| issn | 0968-0896 1464-3391 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | ALK5 inhibitor Alopecia Animals Biological and medical sciences Female Imidazoles - pharmacology Medical sciences Mice Mice, Inbred C57BL Mice, Transgenic Pharmacology. Drug treatments Protein-Serine-Threonine Kinases - antagonists & inhibitors Protein-Serine-Threonine Kinases - chemistry Receptors, Transforming Growth Factor beta - antagonists & inhibitors Receptors, Transforming Growth Factor beta - chemistry Solubility Topical application Transforming growth factor-β |
| title | 5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors |
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