Discovery of Novel Pyrazolo[3,4‑b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension
Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular re...
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Veröffentlicht in: | Journal of medicinal chemistry 2020-10, Vol.63 (19), p.11215-11234 |
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container_title | Journal of medicinal chemistry |
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creator | Hu, Liqing Li, Lijun Chang, Qi Fu, Songsen Qin, Jia Chen, Zhuo Li, Xiaohui Liu, Qinglian Hu, Gaoyun Li, Qianbin |
description | Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery. |
doi_str_mv | 10.1021/acs.jmedchem.0c01132 |
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Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01132</identifier><identifier>PMID: 32914624</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adenylate Kinase - antagonists & inhibitors ; Adenylate Kinase - metabolism ; Animals ; Cell Line ; Drug Design ; Humans ; Hypertension, Pulmonary - drug therapy ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Pyridines - chemistry ; Pyridines - pharmacology ; Rats ; Structure-Activity Relationship ; Vascular Remodeling - drug effects ; Vasodilation - drug effects</subject><ispartof>Journal of medicinal chemistry, 2020-10, Vol.63 (19), p.11215-11234</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a399t-babc33bbd5d83594bd5f4ff952c54aa695767e3952bca93577b15475b55dc09f3</citedby><cites>FETCH-LOGICAL-a399t-babc33bbd5d83594bd5f4ff952c54aa695767e3952bca93577b15475b55dc09f3</cites><orcidid>0000-0003-4522-3067 ; 0000-0002-5434-5747 ; 0000-0003-3592-488X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c01132$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01132$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32914624$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hu, Liqing</creatorcontrib><creatorcontrib>Li, Lijun</creatorcontrib><creatorcontrib>Chang, Qi</creatorcontrib><creatorcontrib>Fu, Songsen</creatorcontrib><creatorcontrib>Qin, Jia</creatorcontrib><creatorcontrib>Chen, Zhuo</creatorcontrib><creatorcontrib>Li, Xiaohui</creatorcontrib><creatorcontrib>Liu, Qinglian</creatorcontrib><creatorcontrib>Hu, Gaoyun</creatorcontrib><creatorcontrib>Li, Qianbin</creatorcontrib><title>Discovery of Novel Pyrazolo[3,4‑b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.</description><subject>Adenylate Kinase - antagonists & inhibitors</subject><subject>Adenylate Kinase - metabolism</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Hypertension, Pulmonary - drug therapy</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><subject>Vascular Remodeling - drug effects</subject><subject>Vasodilation - drug effects</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UctuEzEUtRCIpoU_QMhLFkzwc6azjBpoK1VQocIGoZHt8RBXHju1PUFhxS_wM3wQX8JNk7Jk5evjc8691wehF5TMKWH0jTJ5fjva3qzsOCeGUMrZIzSjkpFKnBLxGM0IYaxiNeNH6DjnW0IIp4w_RUectVTUTMzQ76XLJm5s2uI44PdQeXy9TepH9PELfy3-_Pylv-4Q17tg8dImt1HFbWzG311Z4eWkPF4YQFxxAILJZ5XN5FXCH-0Ye-td-IYvw8ppYMSAVeh3lNg7r-6BISZcVhbfJKvKaEPZmVxPfoxBwViLVKApdLnYri3UIYPoGXoyKJ_t88N5gj69e3tzdlFdfTi_PFtcVYq3bam00oZzrXvZn3LZCigGMQytZEYKpepWNnVjOdy1US2XTaOpFI3UUvaGtAM_Qa_2vusU7yabSzfCf1nvVbBxyh0TgtZENrwGqthTTYo5Jzt06-RG2KCjpNsl1kFi3UNi3SExkL08dJg0vP0TPUQEBLIn3MvjlAIs_H_Pv-74qsg</recordid><startdate>20201008</startdate><enddate>20201008</enddate><creator>Hu, Liqing</creator><creator>Li, Lijun</creator><creator>Chang, Qi</creator><creator>Fu, Songsen</creator><creator>Qin, Jia</creator><creator>Chen, Zhuo</creator><creator>Li, Xiaohui</creator><creator>Liu, Qinglian</creator><creator>Hu, Gaoyun</creator><creator>Li, Qianbin</creator><general>American Chemical Society</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><orcidid>https://orcid.org/0000-0003-4522-3067</orcidid><orcidid>https://orcid.org/0000-0002-5434-5747</orcidid><orcidid>https://orcid.org/0000-0003-3592-488X</orcidid></search><sort><creationdate>20201008</creationdate><title>Discovery of Novel Pyrazolo[3,4‑b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension</title><author>Hu, Liqing ; Li, Lijun ; Chang, Qi ; Fu, Songsen ; Qin, Jia ; Chen, Zhuo ; Li, Xiaohui ; Liu, Qinglian ; Hu, Gaoyun ; Li, Qianbin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a399t-babc33bbd5d83594bd5f4ff952c54aa695767e3952bca93577b15475b55dc09f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adenylate Kinase - antagonists & inhibitors</topic><topic>Adenylate Kinase - metabolism</topic><topic>Animals</topic><topic>Cell Line</topic><topic>Drug Design</topic><topic>Humans</topic><topic>Hypertension, Pulmonary - drug therapy</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><topic>Vascular Remodeling - drug effects</topic><topic>Vasodilation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hu, Liqing</creatorcontrib><creatorcontrib>Li, Lijun</creatorcontrib><creatorcontrib>Chang, Qi</creatorcontrib><creatorcontrib>Fu, Songsen</creatorcontrib><creatorcontrib>Qin, Jia</creatorcontrib><creatorcontrib>Chen, Zhuo</creatorcontrib><creatorcontrib>Li, Xiaohui</creatorcontrib><creatorcontrib>Liu, Qinglian</creatorcontrib><creatorcontrib>Hu, Gaoyun</creatorcontrib><creatorcontrib>Li, Qianbin</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hu, Liqing</au><au>Li, Lijun</au><au>Chang, Qi</au><au>Fu, Songsen</au><au>Qin, Jia</au><au>Chen, Zhuo</au><au>Li, Xiaohui</au><au>Liu, Qinglian</au><au>Hu, Gaoyun</au><au>Li, Qianbin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Novel Pyrazolo[3,4‑b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-10-08</date><risdate>2020</risdate><volume>63</volume><issue>19</issue><spage>11215</spage><epage>11234</epage><pages>11215-11234</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-b] pyridine derivatives based on sGC stimulator and AMPK inhibitor scaffolds. In vitro, 2 exhibited moderate vasodilation activity and higher proliferation and migration suppressive effects compared to riociguat. In vivo, 2 significantly decreased right ventricular systolic pressure (RVSP), attenuated pulmonary artery medial thickness (PAMT), and right ventricular hypertrophy (RVH) in hypoxia-induced PAH rat models (i.g.). Given the unique advantages of significant vascular remodeling inhibition and moderate vascular relaxation based on the dual pathway regulation, we proposed 2 as a promising lead for anti-PAH drug discovery.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32914624</pmid><doi>10.1021/acs.jmedchem.0c01132</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0003-4522-3067</orcidid><orcidid>https://orcid.org/0000-0002-5434-5747</orcidid><orcidid>https://orcid.org/0000-0003-3592-488X</orcidid></addata></record> |
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subjects | Adenylate Kinase - antagonists & inhibitors Adenylate Kinase - metabolism Animals Cell Line Drug Design Humans Hypertension, Pulmonary - drug therapy Pyrazoles - chemistry Pyrazoles - pharmacology Pyridines - chemistry Pyridines - pharmacology Rats Structure-Activity Relationship Vascular Remodeling - drug effects Vasodilation - drug effects |
title | Discovery of Novel Pyrazolo[3,4‑b] Pyridine Derivatives with Dual Activities of Vascular Remodeling Inhibition and Vasodilation for the Treatment of Pulmonary Arterial Hypertension |
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