Benzodiazepine Derivatives as Potent Vasopressin V 2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease
Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V receptor (V R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were d...
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| Veröffentlicht in: | Journal of medicinal chemistry 2022-07, Vol.65 (13), p.9295-9311 |
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| container_title | Journal of medicinal chemistry |
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| creator | Cao, Xudong Wang, Peng Yuan, Haoxing Zhang, Haoran He, Yan Fu, Kequan Fang, Qian Liu, Hongli Su, Limin Yin, Long Xu, Pei Xie, Yuyang Xiong, Xiaochun Wang, Junqi Zhu, Xu Guo, Dong |
| description | Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V
receptor (V
R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V
R. Among these derivatives, compound
exhibited potent binding affinity to the V
R (
= 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC
= 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound
in a murine model of ADPKD demonstrated a significantly improved
efficacy compared with the reference compound tolvaptan. Overall, compound
holds therapeutic potential for the treatment of ADPKD. |
| doi_str_mv | 10.1021/acs.jmedchem.2c00567 |
| format | Article |
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receptor (V
R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V
R. Among these derivatives, compound
exhibited potent binding affinity to the V
R (
= 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC
= 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound
in a murine model of ADPKD demonstrated a significantly improved
efficacy compared with the reference compound tolvaptan. Overall, compound
holds therapeutic potential for the treatment of ADPKD.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.2c00567</identifier><identifier>PMID: 35579344</identifier><language>eng</language><publisher>United States</publisher><ispartof>Journal of medicinal chemistry, 2022-07, Vol.65 (13), p.9295-9311</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c1194-46161aab18549828de9390fb7e15ee94665867223b060d64f2678df26c383a843</citedby><cites>FETCH-LOGICAL-c1194-46161aab18549828de9390fb7e15ee94665867223b060d64f2678df26c383a843</cites><orcidid>0000-0001-6142-4825</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,2766,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35579344$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cao, Xudong</creatorcontrib><creatorcontrib>Wang, Peng</creatorcontrib><creatorcontrib>Yuan, Haoxing</creatorcontrib><creatorcontrib>Zhang, Haoran</creatorcontrib><creatorcontrib>He, Yan</creatorcontrib><creatorcontrib>Fu, Kequan</creatorcontrib><creatorcontrib>Fang, Qian</creatorcontrib><creatorcontrib>Liu, Hongli</creatorcontrib><creatorcontrib>Su, Limin</creatorcontrib><creatorcontrib>Yin, Long</creatorcontrib><creatorcontrib>Xu, Pei</creatorcontrib><creatorcontrib>Xie, Yuyang</creatorcontrib><creatorcontrib>Xiong, Xiaochun</creatorcontrib><creatorcontrib>Wang, Junqi</creatorcontrib><creatorcontrib>Zhu, Xu</creatorcontrib><creatorcontrib>Guo, Dong</creatorcontrib><title>Benzodiazepine Derivatives as Potent Vasopressin V 2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease</title><title>Journal of medicinal chemistry</title><addtitle>J Med Chem</addtitle><description>Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V
receptor (V
R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V
R. Among these derivatives, compound
exhibited potent binding affinity to the V
R (
= 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC
= 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound
in a murine model of ADPKD demonstrated a significantly improved
efficacy compared with the reference compound tolvaptan. Overall, compound
holds therapeutic potential for the treatment of ADPKD.</description><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNo9kF1PwjAUhhujEUT_gTH9A8N-resuUfyKJBqD3C5lO5MS1i5tIYErf7ojgDfnzTknz3vxIHRLyZASRu91GYbLBqpyAc2QlYSkMjtDfZoykghFxDnqE8JYwiTjPXQVwpIQwinjl6jH0zTLuRB99PsAducqo3fQGgt4DN5sdDQbCFgH_Oki2IhnOrjWQwjG4hlm-AtKaKPzeGSj_nHWhBhw3e1xAXjqQcdmj7kaj9bRBdfoFR67xljdXd9NZWGLxyaADnCNLmq9CnBzzAH6fn6aPr4mk4-Xt8fRJCkpzUUiJJVU6zlVqcgVUxXkPCf1PAOaAuRCylTJjDE-J5JUUtRMZqrqZskV10rwARKH3tK7EDzURetNo_22oKTYCy06ocVJaHEU2mF3B6xdz7vfP3QyyP8AsWZ2MQ</recordid><startdate>20220714</startdate><enddate>20220714</enddate><creator>Cao, Xudong</creator><creator>Wang, Peng</creator><creator>Yuan, Haoxing</creator><creator>Zhang, Haoran</creator><creator>He, Yan</creator><creator>Fu, Kequan</creator><creator>Fang, Qian</creator><creator>Liu, Hongli</creator><creator>Su, Limin</creator><creator>Yin, Long</creator><creator>Xu, Pei</creator><creator>Xie, Yuyang</creator><creator>Xiong, Xiaochun</creator><creator>Wang, Junqi</creator><creator>Zhu, Xu</creator><creator>Guo, Dong</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0001-6142-4825</orcidid></search><sort><creationdate>20220714</creationdate><title>Benzodiazepine Derivatives as Potent Vasopressin V 2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease</title><author>Cao, Xudong ; Wang, Peng ; Yuan, Haoxing ; Zhang, Haoran ; He, Yan ; Fu, Kequan ; Fang, Qian ; Liu, Hongli ; Su, Limin ; Yin, Long ; Xu, Pei ; Xie, Yuyang ; Xiong, Xiaochun ; Wang, Junqi ; Zhu, Xu ; Guo, Dong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1194-46161aab18549828de9390fb7e15ee94665867223b060d64f2678df26c383a843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cao, Xudong</creatorcontrib><creatorcontrib>Wang, Peng</creatorcontrib><creatorcontrib>Yuan, Haoxing</creatorcontrib><creatorcontrib>Zhang, Haoran</creatorcontrib><creatorcontrib>He, Yan</creatorcontrib><creatorcontrib>Fu, Kequan</creatorcontrib><creatorcontrib>Fang, Qian</creatorcontrib><creatorcontrib>Liu, Hongli</creatorcontrib><creatorcontrib>Su, Limin</creatorcontrib><creatorcontrib>Yin, Long</creatorcontrib><creatorcontrib>Xu, Pei</creatorcontrib><creatorcontrib>Xie, Yuyang</creatorcontrib><creatorcontrib>Xiong, Xiaochun</creatorcontrib><creatorcontrib>Wang, Junqi</creatorcontrib><creatorcontrib>Zhu, Xu</creatorcontrib><creatorcontrib>Guo, Dong</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cao, Xudong</au><au>Wang, Peng</au><au>Yuan, Haoxing</au><au>Zhang, Haoran</au><au>He, Yan</au><au>Fu, Kequan</au><au>Fang, Qian</au><au>Liu, Hongli</au><au>Su, Limin</au><au>Yin, Long</au><au>Xu, Pei</au><au>Xie, Yuyang</au><au>Xiong, Xiaochun</au><au>Wang, Junqi</au><au>Zhu, Xu</au><au>Guo, Dong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Benzodiazepine Derivatives as Potent Vasopressin V 2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J Med Chem</addtitle><date>2022-07-14</date><risdate>2022</risdate><volume>65</volume><issue>13</issue><spage>9295</spage><epage>9311</epage><pages>9295-9311</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Cyst formation and enlargement in autosomal dominant kidney disease (ADPKD) is mainly driven by aberrantly increased cytosolic cAMP in renal tubule epithelial cells. Because the vasopressin V
receptor (V
R) regulates intracellular cAMP levels in kidneys, a series of benzodiazepine derivatives were developed targeting the V
R. Among these derivatives, compound
exhibited potent binding affinity to the V
R (
= 9.0 ± 1.5 nM) and efficacious cAMP inhibition (IC
= 9.2 ± 3.0 nM). This led to the suppression of cyst formation and growth in both an MDCK cell model and an embryonic kidney cyst model. Further advancing compound
in a murine model of ADPKD demonstrated a significantly improved
efficacy compared with the reference compound tolvaptan. Overall, compound
holds therapeutic potential for the treatment of ADPKD.</abstract><cop>United States</cop><pmid>35579344</pmid><doi>10.1021/acs.jmedchem.2c00567</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-6142-4825</orcidid></addata></record> |
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| source | ACS Publications |
| title | Benzodiazepine Derivatives as Potent Vasopressin V 2 Receptor Antagonists for the Treatment of Autosomal Dominant Kidney Disease |
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