Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors
[Display omitted] Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective...
Gespeichert in:
| Veröffentlicht in: | Bioorganic & medicinal chemistry 2016-12, Vol.24 (23), p.6149-6165 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 6165 |
|---|---|
| container_issue | 23 |
| container_start_page | 6149 |
| container_title | Bioorganic & medicinal chemistry |
| container_volume | 24 |
| creator | Nara, Hiroshi Sato, Kenjiro Kaieda, Akira Oki, Hideyuki Kuno, Haruhiko Santou, Takashi Kanzaki, Naoyuki Terauchi, Jun Uchikawa, Osamu Kori, Masakuni |
| description | [Display omitted]
Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1′ binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described. |
| doi_str_mv | 10.1016/j.bmc.2016.09.009 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1839121680</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0968089616306964</els_id><sourcerecordid>1839121680</sourcerecordid><originalsourceid>FETCH-LOGICAL-c353t-89c0418bbf8fbb69d4a2c4e6a07d78bb01a8bc51181b5403bb4030ef3b6096f3</originalsourceid><addsrcrecordid>eNp9kc1uGyEUhVHVqnHSPkA3FctUMi7Mnxl1VaXpj5SoXWSPgLljX4sBF7CV6YP1-YrltMtu4HL57hGcQ8gbwVeCi-79bmUmu6pKueL9ivP-GVmIpmtYXffiOVnwvpOMy767IJcp7TjnVdOLl-SiWsuqbdtqQX5_goQbv6Rp9nlb6rSk2g_UYHBhg1Y7qm3GI-aZhpH6cAS3pPuQweczucXN1s00gYMTCHQ8JBjofo444YAeWMWsjiY86nIG1rBQekafoEnniI90gqydC_tYZNGXG3p9f__jHRM1_YXeMoO-CG0o-i0azCGmV-TFqF2C10_7FXn4fPtw85Xdff_y7ebjHbN1W2cme8sbIY0Z5WhM1w-NrmwDnebrYV3aXGhpbCuEFKZteG1MWTiMtemKd2N9Ra7PsuVpPw-QspowWXBOewiHpIQsRleik7yg4ozaGFKKMKp9MUDHWQmuTmmpnSppqVNaiveqpFVm3j7JH8wEw7-Jv_EU4MMZgPLHI0JUySJ4CwPG4rYaAv5H_g8NC6hl</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1839121680</pqid></control><display><type>article</type><title>Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Nara, Hiroshi ; Sato, Kenjiro ; Kaieda, Akira ; Oki, Hideyuki ; Kuno, Haruhiko ; Santou, Takashi ; Kanzaki, Naoyuki ; Terauchi, Jun ; Uchikawa, Osamu ; Kori, Masakuni</creator><creatorcontrib>Nara, Hiroshi ; Sato, Kenjiro ; Kaieda, Akira ; Oki, Hideyuki ; Kuno, Haruhiko ; Santou, Takashi ; Kanzaki, Naoyuki ; Terauchi, Jun ; Uchikawa, Osamu ; Kori, Masakuni</creatorcontrib><description>[Display omitted]
Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1′ binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2016.09.009</identifier><identifier>PMID: 27825552</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>ADAM17 Protein - antagonists & inhibitors ; Amides - chemical synthesis ; Amides - pharmacokinetics ; Amides - pharmacology ; Animals ; Drug Design ; Fused pyrimidine-2-carboxamide ; Humans ; Matrix metalloproteinase ; Matrix Metalloproteinase 13 - metabolism ; Matrix Metalloproteinase Inhibitors - chemical synthesis ; Matrix Metalloproteinase Inhibitors - pharmacokinetics ; Matrix Metalloproteinase Inhibitors - pharmacology ; Microsomes, Liver - metabolism ; MMP-13 ; Osteoarthritis ; Pyrimidines - chemical synthesis ; Pyrimidines - pharmacokinetics ; Pyrimidines - pharmacology ; Quinazolinones - chemical synthesis ; Quinazolinones - pharmacokinetics ; Quinazolinones - pharmacology ; Rats ; Structure-based drug design ; Triazoles - chemical synthesis ; Triazoles - pharmacokinetics ; Triazoles - pharmacology ; Zinc - chemistry ; Zinc-binding group</subject><ispartof>Bioorganic & medicinal chemistry, 2016-12, Vol.24 (23), p.6149-6165</ispartof><rights>2016</rights><rights>Copyright © 2016. Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-89c0418bbf8fbb69d4a2c4e6a07d78bb01a8bc51181b5403bb4030ef3b6096f3</citedby><cites>FETCH-LOGICAL-c353t-89c0418bbf8fbb69d4a2c4e6a07d78bb01a8bc51181b5403bb4030ef3b6096f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089616306964$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3536,27903,27904,65309</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27825552$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nara, Hiroshi</creatorcontrib><creatorcontrib>Sato, Kenjiro</creatorcontrib><creatorcontrib>Kaieda, Akira</creatorcontrib><creatorcontrib>Oki, Hideyuki</creatorcontrib><creatorcontrib>Kuno, Haruhiko</creatorcontrib><creatorcontrib>Santou, Takashi</creatorcontrib><creatorcontrib>Kanzaki, Naoyuki</creatorcontrib><creatorcontrib>Terauchi, Jun</creatorcontrib><creatorcontrib>Uchikawa, Osamu</creatorcontrib><creatorcontrib>Kori, Masakuni</creatorcontrib><title>Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1′ binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.</description><subject>ADAM17 Protein - antagonists & inhibitors</subject><subject>Amides - chemical synthesis</subject><subject>Amides - pharmacokinetics</subject><subject>Amides - pharmacology</subject><subject>Animals</subject><subject>Drug Design</subject><subject>Fused pyrimidine-2-carboxamide</subject><subject>Humans</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 13 - metabolism</subject><subject>Matrix Metalloproteinase Inhibitors - chemical synthesis</subject><subject>Matrix Metalloproteinase Inhibitors - pharmacokinetics</subject><subject>Matrix Metalloproteinase Inhibitors - pharmacology</subject><subject>Microsomes, Liver - metabolism</subject><subject>MMP-13</subject><subject>Osteoarthritis</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - pharmacology</subject><subject>Quinazolinones - chemical synthesis</subject><subject>Quinazolinones - pharmacokinetics</subject><subject>Quinazolinones - pharmacology</subject><subject>Rats</subject><subject>Structure-based drug design</subject><subject>Triazoles - chemical synthesis</subject><subject>Triazoles - pharmacokinetics</subject><subject>Triazoles - pharmacology</subject><subject>Zinc - chemistry</subject><subject>Zinc-binding group</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1uGyEUhVHVqnHSPkA3FctUMi7Mnxl1VaXpj5SoXWSPgLljX4sBF7CV6YP1-YrltMtu4HL57hGcQ8gbwVeCi-79bmUmu6pKueL9ivP-GVmIpmtYXffiOVnwvpOMy767IJcp7TjnVdOLl-SiWsuqbdtqQX5_goQbv6Rp9nlb6rSk2g_UYHBhg1Y7qm3GI-aZhpH6cAS3pPuQweczucXN1s00gYMTCHQ8JBjofo444YAeWMWsjiY86nIG1rBQekafoEnniI90gqydC_tYZNGXG3p9f__jHRM1_YXeMoO-CG0o-i0azCGmV-TFqF2C10_7FXn4fPtw85Xdff_y7ebjHbN1W2cme8sbIY0Z5WhM1w-NrmwDnebrYV3aXGhpbCuEFKZteG1MWTiMtemKd2N9Ra7PsuVpPw-QspowWXBOewiHpIQsRleik7yg4ozaGFKKMKp9MUDHWQmuTmmpnSppqVNaiveqpFVm3j7JH8wEw7-Jv_EU4MMZgPLHI0JUySJ4CwPG4rYaAv5H_g8NC6hl</recordid><startdate>20161201</startdate><enddate>20161201</enddate><creator>Nara, Hiroshi</creator><creator>Sato, Kenjiro</creator><creator>Kaieda, Akira</creator><creator>Oki, Hideyuki</creator><creator>Kuno, Haruhiko</creator><creator>Santou, Takashi</creator><creator>Kanzaki, Naoyuki</creator><creator>Terauchi, Jun</creator><creator>Uchikawa, Osamu</creator><creator>Kori, Masakuni</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>20161201</creationdate><title>Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors</title><author>Nara, Hiroshi ; Sato, Kenjiro ; Kaieda, Akira ; Oki, Hideyuki ; Kuno, Haruhiko ; Santou, Takashi ; Kanzaki, Naoyuki ; Terauchi, Jun ; Uchikawa, Osamu ; Kori, Masakuni</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-89c0418bbf8fbb69d4a2c4e6a07d78bb01a8bc51181b5403bb4030ef3b6096f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>ADAM17 Protein - antagonists & inhibitors</topic><topic>Amides - chemical synthesis</topic><topic>Amides - pharmacokinetics</topic><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>Drug Design</topic><topic>Fused pyrimidine-2-carboxamide</topic><topic>Humans</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase 13 - metabolism</topic><topic>Matrix Metalloproteinase Inhibitors - chemical synthesis</topic><topic>Matrix Metalloproteinase Inhibitors - pharmacokinetics</topic><topic>Matrix Metalloproteinase Inhibitors - pharmacology</topic><topic>Microsomes, Liver - metabolism</topic><topic>MMP-13</topic><topic>Osteoarthritis</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Pyrimidines - pharmacology</topic><topic>Quinazolinones - chemical synthesis</topic><topic>Quinazolinones - pharmacokinetics</topic><topic>Quinazolinones - pharmacology</topic><topic>Rats</topic><topic>Structure-based drug design</topic><topic>Triazoles - chemical synthesis</topic><topic>Triazoles - pharmacokinetics</topic><topic>Triazoles - pharmacology</topic><topic>Zinc - chemistry</topic><topic>Zinc-binding group</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nara, Hiroshi</creatorcontrib><creatorcontrib>Sato, Kenjiro</creatorcontrib><creatorcontrib>Kaieda, Akira</creatorcontrib><creatorcontrib>Oki, Hideyuki</creatorcontrib><creatorcontrib>Kuno, Haruhiko</creatorcontrib><creatorcontrib>Santou, Takashi</creatorcontrib><creatorcontrib>Kanzaki, Naoyuki</creatorcontrib><creatorcontrib>Terauchi, Jun</creatorcontrib><creatorcontrib>Uchikawa, Osamu</creatorcontrib><creatorcontrib>Kori, Masakuni</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>Nara, Hiroshi</au><au>Sato, Kenjiro</au><au>Kaieda, Akira</au><au>Oki, Hideyuki</au><au>Kuno, Haruhiko</au><au>Santou, Takashi</au><au>Kanzaki, Naoyuki</au><au>Terauchi, Jun</au><au>Uchikawa, Osamu</au><au>Kori, Masakuni</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2016-12-01</date><risdate>2016</risdate><volume>24</volume><issue>23</issue><spage>6149</spage><epage>6165</epage><pages>6149-6165</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Matrix metalloproteinase-13 (MMP-13), a member of the collagenase family of enzymes, has been implicated to play a key role in the pathology of osteoarthritis. Recently, we have reported the discovery of a series of quinazoline-2-carboxamide based non-zinc-binding MMP-13 selective inhibitors, as exemplified by compound 1. We then continued our research of a novel class of zinc-binding inhibitors to obtain follow-up compounds with different physicochemical, pharmacokinetic, and biological activity profiles. In order to design selective MMP-13 inhibitors, we adopted a strategy of connecting a zinc-binding group with the quinazoline-2-carboxamide system, a unique S1′ binder, by an appropriate linker. Among synthesized compounds, a triazolone inhibitor 35 exhibited excellent potency (IC50=0.071nM) and selectivity (greater than 170-fold) over other MMPs (MMP-1, 2, 3, 7, 8, 9, 10, 12, and 14) and tumor necrosis factor-α converting enzyme (TACE). In this article, the design, synthesis, and biological activity of novel zinc-binding MMP-13 inhibitors are described.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27825552</pmid><doi>10.1016/j.bmc.2016.09.009</doi><tpages>17</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2016-12, Vol.24 (23), p.6149-6165 |
| issn | 0968-0896 1464-3391 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1839121680 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | ADAM17 Protein - antagonists & inhibitors Amides - chemical synthesis Amides - pharmacokinetics Amides - pharmacology Animals Drug Design Fused pyrimidine-2-carboxamide Humans Matrix metalloproteinase Matrix Metalloproteinase 13 - metabolism Matrix Metalloproteinase Inhibitors - chemical synthesis Matrix Metalloproteinase Inhibitors - pharmacokinetics Matrix Metalloproteinase Inhibitors - pharmacology Microsomes, Liver - metabolism MMP-13 Osteoarthritis Pyrimidines - chemical synthesis Pyrimidines - pharmacokinetics Pyrimidines - pharmacology Quinazolinones - chemical synthesis Quinazolinones - pharmacokinetics Quinazolinones - pharmacology Rats Structure-based drug design Triazoles - chemical synthesis Triazoles - pharmacokinetics Triazoles - pharmacology Zinc - chemistry Zinc-binding group |
| title | Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T21%3A02%3A58IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Design,%20synthesis,%20and%20biological%20activity%20of%20novel,%20potent,%20and%20highly%20selective%20fused%20pyrimidine-2-carboxamide-4-one-based%20matrix%20metalloproteinase%20(MMP)-13%20zinc-binding%20inhibitors&rft.jtitle=Bioorganic%20&%20medicinal%20chemistry&rft.au=Nara,%20Hiroshi&rft.date=2016-12-01&rft.volume=24&rft.issue=23&rft.spage=6149&rft.epage=6165&rft.pages=6149-6165&rft.issn=0968-0896&rft.eissn=1464-3391&rft_id=info:doi/10.1016/j.bmc.2016.09.009&rft_dat=%3Cproquest_cross%3E1839121680%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1839121680&rft_id=info:pmid/27825552&rft_els_id=S0968089616306964&rfr_iscdi=true |