Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain
Current pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 i...
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| Veröffentlicht in: | European journal of medicinal chemistry 2022-07, Vol.237, p.114413-114413, Article 114413 |
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| container_title | European journal of medicinal chemistry |
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| creator | Wang, Yuxi Hu, Xiaoyue Huang, Han Jin, Zefang Gao, Jian Guo, Yi Zhong, Yi Li, Zhongtang Zong, Xiaolin Wang, Kewei Zhang, Liangren Liu, Zhenming |
| description | Current pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a series of 4-arylthiophene-3-carboxylic acid derivatives for proof-of-concept studies of ANO1-targeted analgesia. These efforts led to the identification of the compound DFBTA, 4-(4-chlorophenyl)-2-(2,5-difluorobenzamido)thiophene-3-carboxylic acid, which displays dramatic ANO1 inhibition with IC50 of 24 nM. DFBTA displays very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50 > 30 μM, hERG IC50 > 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration ( |
| doi_str_mv | 10.1016/j.ejmech.2022.114413 |
| format | Article |
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∙DFBTA shows comparable ANO1 inhibition in vitro (ANO1 IC50 = 24 nM, FPR assay).∙DFBTA shows very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50 > 30 μM, hERG IC50 > 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma).∙DFBTA performs potent oral analgesic efficacy in inflammatory pain models of hyperalgesia induced by complete Freund's adjuvant and allodynia induced by formalin and capsaicin.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2022.114413</identifier><identifier>PMID: 35512566</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Analgesia ; ANO1 ; Inflammatory pain ; Inhibitor ; SAR</subject><ispartof>European journal of medicinal chemistry, 2022-07, Vol.237, p.114413-114413, Article 114413</ispartof><rights>2022 Elsevier Masson SAS</rights><rights>Copyright © 2022 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-b4c274b357807cc4cee939bc3e94882d32dd6a60cc25fd12b6c46478e5d8c4013</citedby><cites>FETCH-LOGICAL-c362t-b4c274b357807cc4cee939bc3e94882d32dd6a60cc25fd12b6c46478e5d8c4013</cites><orcidid>0000-0002-8993-4015 ; 0000-0001-7023-9998</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0223523422003154$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35512566$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Yuxi</creatorcontrib><creatorcontrib>Hu, Xiaoyue</creatorcontrib><creatorcontrib>Huang, Han</creatorcontrib><creatorcontrib>Jin, Zefang</creatorcontrib><creatorcontrib>Gao, Jian</creatorcontrib><creatorcontrib>Guo, Yi</creatorcontrib><creatorcontrib>Zhong, Yi</creatorcontrib><creatorcontrib>Li, Zhongtang</creatorcontrib><creatorcontrib>Zong, Xiaolin</creatorcontrib><creatorcontrib>Wang, Kewei</creatorcontrib><creatorcontrib>Zhang, Liangren</creatorcontrib><creatorcontrib>Liu, Zhenming</creatorcontrib><title>Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>Current pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a series of 4-arylthiophene-3-carboxylic acid derivatives for proof-of-concept studies of ANO1-targeted analgesia. These efforts led to the identification of the compound DFBTA, 4-(4-chlorophenyl)-2-(2,5-difluorobenzamido)thiophene-3-carboxylic acid, which displays dramatic ANO1 inhibition with IC50 of 24 nM. DFBTA displays very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50 > 30 μM, hERG IC50 > 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma). Finally, the analgesic efficacy of ANO1 inhibitor was evaluated in animal models. DFBTA shown comparable efficacy to clinical drugs in all inflammatory pain models induced by complete Freund's adjuvant, formalin, and capsaicin. These works provide a useful tool compound and promising results for ANO1-targenting analgesic development.
[Display omitted]
∙DFBTA shows comparable ANO1 inhibition in vitro (ANO1 IC50 = 24 nM, FPR assay).∙DFBTA shows very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50 > 30 μM, hERG IC50 > 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma).∙DFBTA performs potent oral analgesic efficacy in inflammatory pain models of hyperalgesia induced by complete Freund's adjuvant and allodynia induced by formalin and capsaicin.</description><subject>Analgesia</subject><subject>ANO1</subject><subject>Inflammatory pain</subject><subject>Inhibitor</subject><subject>SAR</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kc2O0zAURi0EYsrAGyDkJZsU_8VJWSCNRjAgVXQDa8u5viGukrjYbqE8Dw86rjIgVqzuwt93rq4PIS85W3PG9Zv9GvcTwrAWTIg150px-YiseKPbSopaPSar8iCrWkh1RZ6ltGeM1Zqxp-RK1jUXtdYr8nt3yH7yv2z2Yaahp6qy8TzmwYfDgDNWsgIbu_DzPHqgFryjDqM_lfwJE7WJ-nnwnc8hpkv95vOOv6VbtI6Gf8kpH50vhRx-2OhoHtBHamc7fsNUwNj3HiycaR9iIfajnSZbmGd6sH5-Tp70dkz44mFek68f3n-5_Vhtd3efbm-2FUgtctUpEI3qZN20rAFQgLiRmw4kblTbCieFc9pqBiDq3nHRaVBaNS3WrgXFuLwmrxfuIYbvR0zZTD4BjqOdMRyTEVpztmFM1yWqlijEkFLE3hyin8rXGc7MxY_Zm8WPufgxi59Se_Ww4dhN6P6W_ggpgXdLAMudJ4_RJPA4AzofEbJxwf9_wz0y5KYw</recordid><startdate>20220705</startdate><enddate>20220705</enddate><creator>Wang, Yuxi</creator><creator>Hu, Xiaoyue</creator><creator>Huang, Han</creator><creator>Jin, Zefang</creator><creator>Gao, Jian</creator><creator>Guo, Yi</creator><creator>Zhong, Yi</creator><creator>Li, Zhongtang</creator><creator>Zong, Xiaolin</creator><creator>Wang, Kewei</creator><creator>Zhang, Liangren</creator><creator>Liu, Zhenming</creator><general>Elsevier Masson SAS</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8993-4015</orcidid><orcidid>https://orcid.org/0000-0001-7023-9998</orcidid></search><sort><creationdate>20220705</creationdate><title>Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain</title><author>Wang, Yuxi ; Hu, Xiaoyue ; Huang, Han ; Jin, Zefang ; Gao, Jian ; Guo, Yi ; Zhong, Yi ; Li, Zhongtang ; Zong, Xiaolin ; Wang, Kewei ; Zhang, Liangren ; Liu, Zhenming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-b4c274b357807cc4cee939bc3e94882d32dd6a60cc25fd12b6c46478e5d8c4013</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Analgesia</topic><topic>ANO1</topic><topic>Inflammatory pain</topic><topic>Inhibitor</topic><topic>SAR</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Yuxi</creatorcontrib><creatorcontrib>Hu, Xiaoyue</creatorcontrib><creatorcontrib>Huang, Han</creatorcontrib><creatorcontrib>Jin, Zefang</creatorcontrib><creatorcontrib>Gao, Jian</creatorcontrib><creatorcontrib>Guo, Yi</creatorcontrib><creatorcontrib>Zhong, Yi</creatorcontrib><creatorcontrib>Li, Zhongtang</creatorcontrib><creatorcontrib>Zong, Xiaolin</creatorcontrib><creatorcontrib>Wang, Kewei</creatorcontrib><creatorcontrib>Zhang, Liangren</creatorcontrib><creatorcontrib>Liu, Zhenming</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Yuxi</au><au>Hu, Xiaoyue</au><au>Huang, Han</au><au>Jin, Zefang</au><au>Gao, Jian</au><au>Guo, Yi</au><au>Zhong, Yi</au><au>Li, Zhongtang</au><au>Zong, Xiaolin</au><au>Wang, Kewei</au><au>Zhang, Liangren</au><au>Liu, Zhenming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2022-07-05</date><risdate>2022</risdate><volume>237</volume><spage>114413</spage><epage>114413</epage><pages>114413-114413</pages><artnum>114413</artnum><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>Current pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a series of 4-arylthiophene-3-carboxylic acid derivatives for proof-of-concept studies of ANO1-targeted analgesia. These efforts led to the identification of the compound DFBTA, 4-(4-chlorophenyl)-2-(2,5-difluorobenzamido)thiophene-3-carboxylic acid, which displays dramatic ANO1 inhibition with IC50 of 24 nM. DFBTA displays very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50 > 30 μM, hERG IC50 > 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma). Finally, the analgesic efficacy of ANO1 inhibitor was evaluated in animal models. DFBTA shown comparable efficacy to clinical drugs in all inflammatory pain models induced by complete Freund's adjuvant, formalin, and capsaicin. These works provide a useful tool compound and promising results for ANO1-targenting analgesic development.
[Display omitted]
∙DFBTA shows comparable ANO1 inhibition in vitro (ANO1 IC50 = 24 nM, FPR assay).∙DFBTA shows very weak cytotoxicity, cardiotoxicity, and acute toxicity (HEK293 proliferation IC50 > 30 μM, hERG IC50 > 30 μM, mouse minimum lethal dosage, MLD>1000 mg/kg), as well as excellent pharmacokinetics properties with oral bioavailability >75% and little brain penetration (<1.5% brain/plasma).∙DFBTA performs potent oral analgesic efficacy in inflammatory pain models of hyperalgesia induced by complete Freund's adjuvant and allodynia induced by formalin and capsaicin.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>35512566</pmid><doi>10.1016/j.ejmech.2022.114413</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8993-4015</orcidid><orcidid>https://orcid.org/0000-0001-7023-9998</orcidid></addata></record> |
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| language | eng |
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| source | Elsevier ScienceDirect Journals |
| subjects | Analgesia ANO1 Inflammatory pain Inhibitor SAR |
| title | Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain |
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