Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies
[Display omitted] •SAR optimization is explored on a series of phenylpyrazole amides in the discovery of dual ROCK1 and ROCK2 inhibitors.•ROCK1 and ROCK2 co-crystal structures of a dual inhibitor are described.•An in vivo tool molecule which demonstrates good potency, kinome selectivity, and favorab...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2020-11, Vol.30 (21), p.127495-127495, Article 127495 |
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| creator | Hu, Zilun Wang, Cailan Glunz, Peter W. Li, Julia Cheadle, Nathan L. Chen, Alice Y. Chen, Xue-Qing Myers, Joseph E. Guarino, Victor R. Rose, Anne Sack, John S. Sitkoff, Doree Taylor, David S. Xu, Songmei Yan, Chunhong Zhang, Hongwei Zhang, Lisa Hennan, James Adam, Leonard P. Wexler, Ruth R. Quan, Mimi L. |
| description | [Display omitted]
•SAR optimization is explored on a series of phenylpyrazole amides in the discovery of dual ROCK1 and ROCK2 inhibitors.•ROCK1 and ROCK2 co-crystal structures of a dual inhibitor are described.•An in vivo tool molecule which demonstrates good potency, kinome selectivity, and favorable pharmacokinetic profile is identified.•The tool molecule is evaluated for hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure are observed.
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed. |
| doi_str_mv | 10.1016/j.bmcl.2020.127495 |
| format | Article |
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•SAR optimization is explored on a series of phenylpyrazole amides in the discovery of dual ROCK1 and ROCK2 inhibitors.•ROCK1 and ROCK2 co-crystal structures of a dual inhibitor are described.•An in vivo tool molecule which demonstrates good potency, kinome selectivity, and favorable pharmacokinetic profile is identified.•The tool molecule is evaluated for hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure are observed.
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2020.127495</identifier><identifier>PMID: 32798651</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Dual inhibitor ; Phenylpyrazole ; Rho kinase inhibitor ; ROCK ; Telemetry study</subject><ispartof>Bioorganic & medicinal chemistry letters, 2020-11, Vol.30 (21), p.127495-127495, Article 127495</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-c356t-2f09250341a427e5fa2d0c72b14cd77fc342413db34c6408a8a2d8c280782bee3</citedby><cites>FETCH-LOGICAL-c356t-2f09250341a427e5fa2d0c72b14cd77fc342413db34c6408a8a2d8c280782bee3</cites><orcidid>0000-0001-5234-3791</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X20306065$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32798651$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Zilun</creatorcontrib><creatorcontrib>Wang, Cailan</creatorcontrib><creatorcontrib>Glunz, Peter W.</creatorcontrib><creatorcontrib>Li, Julia</creatorcontrib><creatorcontrib>Cheadle, Nathan L.</creatorcontrib><creatorcontrib>Chen, Alice Y.</creatorcontrib><creatorcontrib>Chen, Xue-Qing</creatorcontrib><creatorcontrib>Myers, Joseph E.</creatorcontrib><creatorcontrib>Guarino, Victor R.</creatorcontrib><creatorcontrib>Rose, Anne</creatorcontrib><creatorcontrib>Sack, John S.</creatorcontrib><creatorcontrib>Sitkoff, Doree</creatorcontrib><creatorcontrib>Taylor, David S.</creatorcontrib><creatorcontrib>Xu, Songmei</creatorcontrib><creatorcontrib>Yan, Chunhong</creatorcontrib><creatorcontrib>Zhang, Hongwei</creatorcontrib><creatorcontrib>Zhang, Lisa</creatorcontrib><creatorcontrib>Hennan, James</creatorcontrib><creatorcontrib>Adam, Leonard P.</creatorcontrib><creatorcontrib>Wexler, Ruth R.</creatorcontrib><creatorcontrib>Quan, Mimi L.</creatorcontrib><title>Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
•SAR optimization is explored on a series of phenylpyrazole amides in the discovery of dual ROCK1 and ROCK2 inhibitors.•ROCK1 and ROCK2 co-crystal structures of a dual inhibitor are described.•An in vivo tool molecule which demonstrates good potency, kinome selectivity, and favorable pharmacokinetic profile is identified.•The tool molecule is evaluated for hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure are observed.
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.</description><subject>Dual inhibitor</subject><subject>Phenylpyrazole</subject><subject>Rho kinase inhibitor</subject><subject>ROCK</subject><subject>Telemetry study</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kE1r20AURYeQUrtu_0AWYZbZyJmPJ40E2QSnbUINhtJAuxpGoyc8RtK4M5LB-fUd4zTLrB5czr3wDiFXnC0548Xtbln3tlsKJlIgFFT5BZlzKCCTwPJLMmdVwbKygt8z8inGHWMcGMBHMpNCVWWR8zn58-Ci9QcMR-pbauh-i8Ox2x-DefEdUtO7BunPzeoHdcPW1W70gZqYwNH7jvaJsVPi2hS7gR7cwdM4To3D-Jl8aE0X8cvrXZDnb19_rR6z9eb70-p-nVmZF2MmWlaJnEngBoTCvDWiYVaJmoNtlGqtBAFcNrUEWwArTZmA0oqSqVLUiHJBbs67--D_ThhH3aeXsOvMgH6KWoAElQvFZELFGbXBxxiw1fvgehOOmjN9Uqp3-qRUn5Tqs9JUun7dn-oem7fKf4cJuDsDmL48OAw6WoeDxcYFtKNuvHtv_x8rY4bs</recordid><startdate>20201101</startdate><enddate>20201101</enddate><creator>Hu, Zilun</creator><creator>Wang, Cailan</creator><creator>Glunz, Peter W.</creator><creator>Li, Julia</creator><creator>Cheadle, Nathan L.</creator><creator>Chen, Alice Y.</creator><creator>Chen, Xue-Qing</creator><creator>Myers, Joseph E.</creator><creator>Guarino, Victor R.</creator><creator>Rose, Anne</creator><creator>Sack, John S.</creator><creator>Sitkoff, Doree</creator><creator>Taylor, David S.</creator><creator>Xu, Songmei</creator><creator>Yan, Chunhong</creator><creator>Zhang, Hongwei</creator><creator>Zhang, Lisa</creator><creator>Hennan, James</creator><creator>Adam, Leonard P.</creator><creator>Wexler, Ruth R.</creator><creator>Quan, Mimi L.</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5234-3791</orcidid></search><sort><creationdate>20201101</creationdate><title>Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies</title><author>Hu, Zilun ; Wang, Cailan ; Glunz, Peter W. ; Li, Julia ; Cheadle, Nathan L. ; Chen, Alice Y. ; Chen, Xue-Qing ; Myers, Joseph E. ; Guarino, Victor R. ; Rose, Anne ; Sack, John S. ; Sitkoff, Doree ; Taylor, David S. ; Xu, Songmei ; Yan, Chunhong ; Zhang, Hongwei ; Zhang, Lisa ; Hennan, James ; Adam, Leonard P. ; Wexler, Ruth R. ; Quan, Mimi L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-2f09250341a427e5fa2d0c72b14cd77fc342413db34c6408a8a2d8c280782bee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Dual inhibitor</topic><topic>Phenylpyrazole</topic><topic>Rho kinase inhibitor</topic><topic>ROCK</topic><topic>Telemetry study</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Zilun</creatorcontrib><creatorcontrib>Wang, Cailan</creatorcontrib><creatorcontrib>Glunz, Peter W.</creatorcontrib><creatorcontrib>Li, Julia</creatorcontrib><creatorcontrib>Cheadle, Nathan L.</creatorcontrib><creatorcontrib>Chen, Alice Y.</creatorcontrib><creatorcontrib>Chen, Xue-Qing</creatorcontrib><creatorcontrib>Myers, Joseph E.</creatorcontrib><creatorcontrib>Guarino, Victor R.</creatorcontrib><creatorcontrib>Rose, Anne</creatorcontrib><creatorcontrib>Sack, John S.</creatorcontrib><creatorcontrib>Sitkoff, Doree</creatorcontrib><creatorcontrib>Taylor, David S.</creatorcontrib><creatorcontrib>Xu, Songmei</creatorcontrib><creatorcontrib>Yan, Chunhong</creatorcontrib><creatorcontrib>Zhang, Hongwei</creatorcontrib><creatorcontrib>Zhang, Lisa</creatorcontrib><creatorcontrib>Hennan, James</creatorcontrib><creatorcontrib>Adam, Leonard P.</creatorcontrib><creatorcontrib>Wexler, Ruth R.</creatorcontrib><creatorcontrib>Quan, Mimi L.</creatorcontrib><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>Hu, Zilun</au><au>Wang, Cailan</au><au>Glunz, Peter W.</au><au>Li, Julia</au><au>Cheadle, Nathan L.</au><au>Chen, Alice Y.</au><au>Chen, Xue-Qing</au><au>Myers, Joseph E.</au><au>Guarino, Victor R.</au><au>Rose, Anne</au><au>Sack, John S.</au><au>Sitkoff, Doree</au><au>Taylor, David S.</au><au>Xu, Songmei</au><au>Yan, Chunhong</au><au>Zhang, Hongwei</au><au>Zhang, Lisa</au><au>Hennan, James</au><au>Adam, Leonard P.</au><au>Wexler, Ruth R.</au><au>Quan, Mimi L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2020-11-01</date><risdate>2020</risdate><volume>30</volume><issue>21</issue><spage>127495</spage><epage>127495</epage><pages>127495-127495</pages><artnum>127495</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
•SAR optimization is explored on a series of phenylpyrazole amides in the discovery of dual ROCK1 and ROCK2 inhibitors.•ROCK1 and ROCK2 co-crystal structures of a dual inhibitor are described.•An in vivo tool molecule which demonstrates good potency, kinome selectivity, and favorable pharmacokinetic profile is identified.•The tool molecule is evaluated for hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure are observed.
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>32798651</pmid><doi>10.1016/j.bmcl.2020.127495</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0001-5234-3791</orcidid></addata></record> |
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| subjects | Dual inhibitor Phenylpyrazole Rho kinase inhibitor ROCK Telemetry study |
| title | Discovery of a phenylpyrazole amide ROCK inhibitor as a tool molecule for in vivo studies |
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