Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists
[Display omitted] An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic intera...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (16), p.2265-2269 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Lu, Zhonghui Duan, James J.-W. Xiao, Haiyun Neels, James Wu, Dauh-Rurng Weigelt, Carolyn A. Sack, John S. Khan, Javed Ruzanov, Max An, Yongmi Yarde, Melissa Karmakar, Ananta Vishwakrishnan, Sureshbabu Baratam, Venkata Shankarappa, Harisha Vanteru, Sridhar Babu, Venkatesh Basha, Mushkin Kumar Gupta, Arun Kumaravel, Selvakumar Mathur, Arvind Zhao, Qihong Salter-Cid, Luisa M. Carter, Percy H. Murali Dhar, T.G. |
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An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2. |
| doi_str_mv | 10.1016/j.bmcl.2019.06.036 |
| format | Article |
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An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2019.06.036</identifier><identifier>PMID: 31257087</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>IL-17 ; Inverse agonist ; Retinoic acid-related orphan receptor gamma t ; RORγt ; Th17</subject><ispartof>Bioorganic & medicinal chemistry letters, 2019-08, Vol.29 (16), p.2265-2269</ispartof><rights>2019 Elsevier Ltd</rights><rights>Copyright © 2019 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-7127363802f810f4637500bb2359372ef28d0d1f6ee4ce8490b62f584e9645da3</citedby><cites>FETCH-LOGICAL-c356t-7127363802f810f4637500bb2359372ef28d0d1f6ee4ce8490b62f584e9645da3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X19304160$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31257087$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lu, Zhonghui</creatorcontrib><creatorcontrib>Duan, James J.-W.</creatorcontrib><creatorcontrib>Xiao, Haiyun</creatorcontrib><creatorcontrib>Neels, James</creatorcontrib><creatorcontrib>Wu, Dauh-Rurng</creatorcontrib><creatorcontrib>Weigelt, Carolyn A.</creatorcontrib><creatorcontrib>Sack, John S.</creatorcontrib><creatorcontrib>Khan, Javed</creatorcontrib><creatorcontrib>Ruzanov, Max</creatorcontrib><creatorcontrib>An, Yongmi</creatorcontrib><creatorcontrib>Yarde, Melissa</creatorcontrib><creatorcontrib>Karmakar, Ananta</creatorcontrib><creatorcontrib>Vishwakrishnan, Sureshbabu</creatorcontrib><creatorcontrib>Baratam, Venkata</creatorcontrib><creatorcontrib>Shankarappa, Harisha</creatorcontrib><creatorcontrib>Vanteru, Sridhar</creatorcontrib><creatorcontrib>Babu, Venkatesh</creatorcontrib><creatorcontrib>Basha, Mushkin</creatorcontrib><creatorcontrib>Kumar Gupta, Arun</creatorcontrib><creatorcontrib>Kumaravel, Selvakumar</creatorcontrib><creatorcontrib>Mathur, Arvind</creatorcontrib><creatorcontrib>Zhao, Qihong</creatorcontrib><creatorcontrib>Salter-Cid, Luisa M.</creatorcontrib><creatorcontrib>Carter, Percy H.</creatorcontrib><creatorcontrib>Murali Dhar, T.G.</creatorcontrib><title>Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.</description><subject>IL-17</subject><subject>Inverse agonist</subject><subject>Retinoic acid-related orphan receptor gamma t</subject><subject>RORγt</subject><subject>Th17</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9UUuK3DAQFSEh09PJBbIIWvbA2Cl9LNuQzTDkMzAw0CSQnZDt8kSNWnIkd4PvkNvkHjlT1PQky6yKqnr1quo9Qt4wKBkw9W5XdvvelRxYW4IqQahnZMWkkoWQUD0nK2gVFE0rv12Qy5R2AEyClC_JhWC8qqGpV-Tn3YB-tqPtzWyDp2GkU5hz6ZomdNjP9ojU-IGGaJxbaGeDORrrTOeQTt_RL45uNturQhTnbFpiDM4O1ufS4q7SwY3BnziMC48HTNQkun3Y_v41U-uPGFPuPQZv05xekRejcQlfP8U1-frxw5fbz8X9w6e725v7oheVmoua8Voo0QAfGwajVKKuALqOi6oVNceRNwMMbFSIssdGttApPlaNxFbJajBiTTZn3imGH_mkWe9t6tE54zEckua8AiV4ndesCT9D-xhSijjqKdq9iYtmoE8u6J0-uaBPLmhQOruQh94-8R-6PQ7_Rv7KngHvzwDMXx4tRp16i77HwcasuR6C_R__HyRdmm0</recordid><startdate>20190815</startdate><enddate>20190815</enddate><creator>Lu, Zhonghui</creator><creator>Duan, James J.-W.</creator><creator>Xiao, Haiyun</creator><creator>Neels, James</creator><creator>Wu, Dauh-Rurng</creator><creator>Weigelt, Carolyn A.</creator><creator>Sack, John S.</creator><creator>Khan, Javed</creator><creator>Ruzanov, Max</creator><creator>An, Yongmi</creator><creator>Yarde, Melissa</creator><creator>Karmakar, Ananta</creator><creator>Vishwakrishnan, Sureshbabu</creator><creator>Baratam, Venkata</creator><creator>Shankarappa, Harisha</creator><creator>Vanteru, Sridhar</creator><creator>Babu, Venkatesh</creator><creator>Basha, Mushkin</creator><creator>Kumar Gupta, Arun</creator><creator>Kumaravel, Selvakumar</creator><creator>Mathur, Arvind</creator><creator>Zhao, Qihong</creator><creator>Salter-Cid, Luisa M.</creator><creator>Carter, Percy H.</creator><creator>Murali Dhar, T.G.</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20190815</creationdate><title>Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists</title><author>Lu, Zhonghui ; Duan, James J.-W. ; Xiao, Haiyun ; Neels, James ; Wu, Dauh-Rurng ; Weigelt, Carolyn A. ; Sack, John S. ; Khan, Javed ; Ruzanov, Max ; An, Yongmi ; Yarde, Melissa ; Karmakar, Ananta ; Vishwakrishnan, Sureshbabu ; Baratam, Venkata ; Shankarappa, Harisha ; Vanteru, Sridhar ; Babu, Venkatesh ; Basha, Mushkin ; Kumar Gupta, Arun ; Kumaravel, Selvakumar ; Mathur, Arvind ; Zhao, Qihong ; Salter-Cid, Luisa M. ; Carter, Percy H. ; Murali Dhar, T.G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-7127363802f810f4637500bb2359372ef28d0d1f6ee4ce8490b62f584e9645da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>IL-17</topic><topic>Inverse agonist</topic><topic>Retinoic acid-related orphan receptor gamma t</topic><topic>RORγt</topic><topic>Th17</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lu, Zhonghui</creatorcontrib><creatorcontrib>Duan, James J.-W.</creatorcontrib><creatorcontrib>Xiao, Haiyun</creatorcontrib><creatorcontrib>Neels, James</creatorcontrib><creatorcontrib>Wu, Dauh-Rurng</creatorcontrib><creatorcontrib>Weigelt, Carolyn A.</creatorcontrib><creatorcontrib>Sack, John S.</creatorcontrib><creatorcontrib>Khan, Javed</creatorcontrib><creatorcontrib>Ruzanov, Max</creatorcontrib><creatorcontrib>An, Yongmi</creatorcontrib><creatorcontrib>Yarde, Melissa</creatorcontrib><creatorcontrib>Karmakar, Ananta</creatorcontrib><creatorcontrib>Vishwakrishnan, Sureshbabu</creatorcontrib><creatorcontrib>Baratam, Venkata</creatorcontrib><creatorcontrib>Shankarappa, Harisha</creatorcontrib><creatorcontrib>Vanteru, Sridhar</creatorcontrib><creatorcontrib>Babu, Venkatesh</creatorcontrib><creatorcontrib>Basha, Mushkin</creatorcontrib><creatorcontrib>Kumar Gupta, Arun</creatorcontrib><creatorcontrib>Kumaravel, Selvakumar</creatorcontrib><creatorcontrib>Mathur, Arvind</creatorcontrib><creatorcontrib>Zhao, Qihong</creatorcontrib><creatorcontrib>Salter-Cid, Luisa M.</creatorcontrib><creatorcontrib>Carter, Percy H.</creatorcontrib><creatorcontrib>Murali Dhar, T.G.</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>Lu, Zhonghui</au><au>Duan, James J.-W.</au><au>Xiao, Haiyun</au><au>Neels, James</au><au>Wu, Dauh-Rurng</au><au>Weigelt, Carolyn A.</au><au>Sack, John S.</au><au>Khan, Javed</au><au>Ruzanov, Max</au><au>An, Yongmi</au><au>Yarde, Melissa</au><au>Karmakar, Ananta</au><au>Vishwakrishnan, Sureshbabu</au><au>Baratam, Venkata</au><au>Shankarappa, Harisha</au><au>Vanteru, Sridhar</au><au>Babu, Venkatesh</au><au>Basha, Mushkin</au><au>Kumar Gupta, Arun</au><au>Kumaravel, Selvakumar</au><au>Mathur, Arvind</au><au>Zhao, Qihong</au><au>Salter-Cid, Luisa M.</au><au>Carter, Percy H.</au><au>Murali Dhar, T.G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2019-08-15</date><risdate>2019</risdate><volume>29</volume><issue>16</issue><spage>2265</spage><epage>2269</epage><pages>2265-2269</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31257087</pmid><doi>10.1016/j.bmcl.2019.06.036</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2019-08, Vol.29 (16), p.2265-2269 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2250632727 |
| source | Elsevier ScienceDirect Journals |
| subjects | IL-17 Inverse agonist Retinoic acid-related orphan receptor gamma t RORγt Th17 |
| title | Identification of potent, selective and orally bioavailable phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone analogues as RORγt inverse agonists |
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