Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors
[Display omitted] Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-06, Vol.27 (11), p.2622-2628 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 27 |
| creator | Sakurada, Isao Endo, Toshiya Hikita, Katsuyoshi Hirabayashi, Tomokazu Hosaka, Yoshitaka Kato, Yutaka Maeda, Yoshitaka Matsumoto, Shigeki Mizuno, Takashi Nagasue, Hiroshi Nishimura, Teruyuki Shimada, Shunsuke Shinozaki, Mikihiko Taguchi, Keiko Takeuchi, Katsutoshi Yokoyama, Tooru Hruza, Alan Reichert, Paul Zhang, Ting Wood, Harold B. Nakao, Kazunari Furusako, Shoji |
| description | [Display omitted]
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated. |
| doi_str_mv | 10.1016/j.bmcl.2017.03.002 |
| format | Article |
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Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.03.002</identifier><identifier>PMID: 28408226</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>60 APPLIED LIFE SCIENCES ; Aminobenzisoxazole ; Animals ; Anticoagulant ; Azabicyclic ring ; Binding Sites ; Blood Coagulation - drug effects ; Crystallography, X-Ray ; Dogs ; Drug Design ; Drug Evaluation, Preclinical ; Factor IXa - antagonists & inhibitors ; Factor IXa - metabolism ; Factor IXa inhibitor ; Half-Life ; Humans ; Inhibitory Concentration 50 ; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY ; Isoxazoles - chemistry ; Isoxazoles - metabolism ; Isoxazoles - pharmacology ; Molecular Dynamics Simulation ; Partial Thromboplastin Time ; Protein Structure, Tertiary ; Prothrombin Time ; Rats ; Structure based drug design ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-06, Vol.27 (11), p.2622-2628</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c383t-57cc17d681c4fa9345b977d3658e9f27f39c514fe044dd194a19d6b34f53670b3</citedby><cites>FETCH-LOGICAL-c383t-57cc17d681c4fa9345b977d3658e9f27f39c514fe044dd194a19d6b34f53670b3</cites><orcidid>0000-0002-4445-8318 ; 0000000244458318</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X17302251$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28408226$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1404976$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Sakurada, Isao</creatorcontrib><creatorcontrib>Endo, Toshiya</creatorcontrib><creatorcontrib>Hikita, Katsuyoshi</creatorcontrib><creatorcontrib>Hirabayashi, Tomokazu</creatorcontrib><creatorcontrib>Hosaka, Yoshitaka</creatorcontrib><creatorcontrib>Kato, Yutaka</creatorcontrib><creatorcontrib>Maeda, Yoshitaka</creatorcontrib><creatorcontrib>Matsumoto, Shigeki</creatorcontrib><creatorcontrib>Mizuno, Takashi</creatorcontrib><creatorcontrib>Nagasue, Hiroshi</creatorcontrib><creatorcontrib>Nishimura, Teruyuki</creatorcontrib><creatorcontrib>Shimada, Shunsuke</creatorcontrib><creatorcontrib>Shinozaki, Mikihiko</creatorcontrib><creatorcontrib>Taguchi, Keiko</creatorcontrib><creatorcontrib>Takeuchi, Katsutoshi</creatorcontrib><creatorcontrib>Yokoyama, Tooru</creatorcontrib><creatorcontrib>Hruza, Alan</creatorcontrib><creatorcontrib>Reichert, Paul</creatorcontrib><creatorcontrib>Zhang, Ting</creatorcontrib><creatorcontrib>Wood, Harold B.</creatorcontrib><creatorcontrib>Nakao, Kazunari</creatorcontrib><creatorcontrib>Furusako, Shoji</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.</description><subject>60 APPLIED LIFE SCIENCES</subject><subject>Aminobenzisoxazole</subject><subject>Animals</subject><subject>Anticoagulant</subject><subject>Azabicyclic ring</subject><subject>Binding Sites</subject><subject>Blood Coagulation - drug effects</subject><subject>Crystallography, X-Ray</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Drug Evaluation, Preclinical</subject><subject>Factor IXa - antagonists & inhibitors</subject><subject>Factor IXa - metabolism</subject><subject>Factor IXa inhibitor</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</subject><subject>Isoxazoles - chemistry</subject><subject>Isoxazoles - metabolism</subject><subject>Isoxazoles - pharmacology</subject><subject>Molecular Dynamics Simulation</subject><subject>Partial Thromboplastin Time</subject><subject>Protein Structure, Tertiary</subject><subject>Prothrombin Time</subject><subject>Rats</subject><subject>Structure based drug design</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFuFSEUhonR2Gv1BVwY4srNjDAwMCRuTKu1SRM3mjRxQRg4pNwwQ4W5E2-fXia3dukKCN_5858PobeUtJRQ8XHfjpONbUeobAlrCemeoR3lgjeMk_452hElSDMofnuGXpWyJ4RywvlLdNYNnAxdJ3bo12UoNq2Qjzh5PNdbxGYKcxphfggl_TEPKQJ2kMNqlrBCwabglE2MR2xWE6IZ6783dkkZX98aHOa7MIb6Kq_RC29igTeP5zn6-fXLj4tvzc33q-uLzzeNZQNbml5aS6UTA7XcG8V4PyopHRP9AMp30jNle8o91O7OUcUNVU6MjPueCUlGdo7en3JTWYIuNixg72yaZ7CL3lZWUlTowwm6z-n3Acqip7o5xGhmSIei6TAMQipJu4p2J9TmVEoGr-9zmEw-akr0Zl7v9WZeb-Y1Ybqar0PvHvMP4wTuaeSf6gp8OgFQVawB8tYUZgsu5K2oS-F_-X8BFWKU9g</recordid><startdate>20170601</startdate><enddate>20170601</enddate><creator>Sakurada, Isao</creator><creator>Endo, Toshiya</creator><creator>Hikita, Katsuyoshi</creator><creator>Hirabayashi, Tomokazu</creator><creator>Hosaka, Yoshitaka</creator><creator>Kato, Yutaka</creator><creator>Maeda, Yoshitaka</creator><creator>Matsumoto, Shigeki</creator><creator>Mizuno, Takashi</creator><creator>Nagasue, Hiroshi</creator><creator>Nishimura, Teruyuki</creator><creator>Shimada, Shunsuke</creator><creator>Shinozaki, Mikihiko</creator><creator>Taguchi, Keiko</creator><creator>Takeuchi, Katsutoshi</creator><creator>Yokoyama, Tooru</creator><creator>Hruza, Alan</creator><creator>Reichert, Paul</creator><creator>Zhang, Ting</creator><creator>Wood, Harold B.</creator><creator>Nakao, Kazunari</creator><creator>Furusako, Shoji</creator><general>Elsevier Ltd</general><general>Elsevier</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><scope>OTOTI</scope><orcidid>https://orcid.org/0000-0002-4445-8318</orcidid><orcidid>https://orcid.org/0000000244458318</orcidid></search><sort><creationdate>20170601</creationdate><title>Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors</title><author>Sakurada, Isao ; Endo, Toshiya ; Hikita, Katsuyoshi ; Hirabayashi, Tomokazu ; Hosaka, Yoshitaka ; Kato, Yutaka ; Maeda, Yoshitaka ; Matsumoto, Shigeki ; Mizuno, Takashi ; Nagasue, Hiroshi ; Nishimura, Teruyuki ; Shimada, Shunsuke ; Shinozaki, Mikihiko ; Taguchi, Keiko ; Takeuchi, Katsutoshi ; Yokoyama, Tooru ; Hruza, Alan ; Reichert, Paul ; Zhang, Ting ; Wood, Harold B. ; Nakao, Kazunari ; Furusako, Shoji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c383t-57cc17d681c4fa9345b977d3658e9f27f39c514fe044dd194a19d6b34f53670b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>60 APPLIED LIFE SCIENCES</topic><topic>Aminobenzisoxazole</topic><topic>Animals</topic><topic>Anticoagulant</topic><topic>Azabicyclic ring</topic><topic>Binding Sites</topic><topic>Blood Coagulation - drug effects</topic><topic>Crystallography, X-Ray</topic><topic>Dogs</topic><topic>Drug Design</topic><topic>Drug Evaluation, Preclinical</topic><topic>Factor IXa - antagonists & inhibitors</topic><topic>Factor IXa - metabolism</topic><topic>Factor IXa inhibitor</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY</topic><topic>Isoxazoles - chemistry</topic><topic>Isoxazoles - metabolism</topic><topic>Isoxazoles - pharmacology</topic><topic>Molecular Dynamics Simulation</topic><topic>Partial Thromboplastin Time</topic><topic>Protein Structure, Tertiary</topic><topic>Prothrombin Time</topic><topic>Rats</topic><topic>Structure based drug design</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sakurada, Isao</creatorcontrib><creatorcontrib>Endo, Toshiya</creatorcontrib><creatorcontrib>Hikita, Katsuyoshi</creatorcontrib><creatorcontrib>Hirabayashi, Tomokazu</creatorcontrib><creatorcontrib>Hosaka, Yoshitaka</creatorcontrib><creatorcontrib>Kato, Yutaka</creatorcontrib><creatorcontrib>Maeda, Yoshitaka</creatorcontrib><creatorcontrib>Matsumoto, Shigeki</creatorcontrib><creatorcontrib>Mizuno, Takashi</creatorcontrib><creatorcontrib>Nagasue, Hiroshi</creatorcontrib><creatorcontrib>Nishimura, Teruyuki</creatorcontrib><creatorcontrib>Shimada, Shunsuke</creatorcontrib><creatorcontrib>Shinozaki, Mikihiko</creatorcontrib><creatorcontrib>Taguchi, Keiko</creatorcontrib><creatorcontrib>Takeuchi, Katsutoshi</creatorcontrib><creatorcontrib>Yokoyama, Tooru</creatorcontrib><creatorcontrib>Hruza, Alan</creatorcontrib><creatorcontrib>Reichert, Paul</creatorcontrib><creatorcontrib>Zhang, Ting</creatorcontrib><creatorcontrib>Wood, Harold B.</creatorcontrib><creatorcontrib>Nakao, Kazunari</creatorcontrib><creatorcontrib>Furusako, Shoji</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</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><collection>OSTI.GOV</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sakurada, Isao</au><au>Endo, Toshiya</au><au>Hikita, Katsuyoshi</au><au>Hirabayashi, Tomokazu</au><au>Hosaka, Yoshitaka</au><au>Kato, Yutaka</au><au>Maeda, Yoshitaka</au><au>Matsumoto, Shigeki</au><au>Mizuno, Takashi</au><au>Nagasue, Hiroshi</au><au>Nishimura, Teruyuki</au><au>Shimada, Shunsuke</au><au>Shinozaki, Mikihiko</au><au>Taguchi, Keiko</au><au>Takeuchi, Katsutoshi</au><au>Yokoyama, Tooru</au><au>Hruza, Alan</au><au>Reichert, Paul</au><au>Zhang, Ting</au><au>Wood, Harold B.</au><au>Nakao, Kazunari</au><au>Furusako, Shoji</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-06-01</date><risdate>2017</risdate><volume>27</volume><issue>11</issue><spage>2622</spage><epage>2628</epage><pages>2622-2628</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28408226</pmid><doi>10.1016/j.bmcl.2017.03.002</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-4445-8318</orcidid><orcidid>https://orcid.org/0000000244458318</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2017-06, Vol.27 (11), p.2622-2628 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_osti_scitechconnect_1404976 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 60 APPLIED LIFE SCIENCES Aminobenzisoxazole Animals Anticoagulant Azabicyclic ring Binding Sites Blood Coagulation - drug effects Crystallography, X-Ray Dogs Drug Design Drug Evaluation, Preclinical Factor IXa - antagonists & inhibitors Factor IXa - metabolism Factor IXa inhibitor Half-Life Humans Inhibitory Concentration 50 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY Isoxazoles - chemistry Isoxazoles - metabolism Isoxazoles - pharmacology Molecular Dynamics Simulation Partial Thromboplastin Time Protein Structure, Tertiary Prothrombin Time Rats Structure based drug design Structure-Activity Relationship |
| title | Discovery of novel aminobenzisoxazole derivatives as orally available factor IXa inhibitors |
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