Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition
[Display omitted] Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2017-08, Vol.25 (15), p.4110-4122 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Yamaki, Susumu Koga, Yuji Nagashima, Akira Kondo, Mitsuhiro Shimada, Yoshiaki Kadono, Keitaro Moritomo, Ayako Yoshihara, Kosei |
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Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy. |
| doi_str_mv | 10.1016/j.bmc.2017.05.059 |
| format | Article |
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Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2017.05.059</identifier><identifier>PMID: 28601507</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Amine Oxidase (Copper-Containing) - antagonists & inhibitors ; Animals ; Cell Adhesion Molecules - antagonists & inhibitors ; CYP2C19 ; CYP3A4 ; Cytochrome P-450 CYP2C19 Inhibitors - pharmacology ; Cytochrome P-450 CYP3A Inhibitors - pharmacology ; Diabetic Nephropathies - drug therapy ; Diabetic nephropathy ; Glycine - analogs & derivatives ; Glycine - chemical synthesis ; Glycine - chemistry ; Glycine - pharmacology ; Glycine - therapeutic use ; Glycine amide ; Humans ; Molecular Docking Simulation ; Proton Magnetic Resonance Spectroscopy ; Rats ; Spectrometry, Mass, Electrospray Ionization ; Vascular adhesion protein-1</subject><ispartof>Bioorganic & medicinal chemistry, 2017-08, Vol.25 (15), p.4110-4122</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-c353t-d6737add37715040aec3cd5dbb1fa7d0979f5114671fedf12b1eaa715050987b3</citedby><cites>FETCH-LOGICAL-c353t-d6737add37715040aec3cd5dbb1fa7d0979f5114671fedf12b1eaa715050987b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089617304339$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28601507$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yamaki, Susumu</creatorcontrib><creatorcontrib>Koga, Yuji</creatorcontrib><creatorcontrib>Nagashima, Akira</creatorcontrib><creatorcontrib>Kondo, Mitsuhiro</creatorcontrib><creatorcontrib>Shimada, Yoshiaki</creatorcontrib><creatorcontrib>Kadono, Keitaro</creatorcontrib><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Yoshihara, Kosei</creatorcontrib><title>Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.</description><subject>Amine Oxidase (Copper-Containing) - antagonists & inhibitors</subject><subject>Animals</subject><subject>Cell Adhesion Molecules - antagonists & inhibitors</subject><subject>CYP2C19</subject><subject>CYP3A4</subject><subject>Cytochrome P-450 CYP2C19 Inhibitors - pharmacology</subject><subject>Cytochrome P-450 CYP3A Inhibitors - pharmacology</subject><subject>Diabetic Nephropathies - drug therapy</subject><subject>Diabetic nephropathy</subject><subject>Glycine - analogs & derivatives</subject><subject>Glycine - chemical synthesis</subject><subject>Glycine - chemistry</subject><subject>Glycine - pharmacology</subject><subject>Glycine - therapeutic use</subject><subject>Glycine amide</subject><subject>Humans</subject><subject>Molecular Docking Simulation</subject><subject>Proton Magnetic Resonance Spectroscopy</subject><subject>Rats</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>Vascular adhesion protein-1</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc-KFDEQxoMo7rj6AF4kRy89Jp3uTgdPy-A_WFBQD55CdVK9kyGdjEl3yzyLL2vG2fUoFCRQv-9Lqj5CXnK25Yx3bw7bYTLbmnG5ZW0p9YhseNM1lRCKPyYbprq-Yr3qrsiznA-MsbpR_Cm5qvuO8ZbJDfn99RTmPWaXKQRLj3tIE5jo450z4Cmu4BeYXQw0jvTOn4wLSGFyFqnF5NbSW7FoMw1xRU9XyGbxkCjYs2vRHVOc0YWKUxf2bnBzTJn-cvM-LjPd_fgibpq_T5drvePqgSrS5-TJCD7ji_vzmnx__-7b7mN1-_nDp93NbWVEK-bKdlJIsFZIWWZqGKARxrZ2GPgI0jIl1djyshfJR7QjrweOAGe2ZaqXg7gmry--5as_F8yznlw26D0EjEvWXLFeKtHLvqD8gpoUc0446mNyE6ST5kyfM9EHXTLR50w0a0uponl1b78ME9p_iocQCvD2AmAZcnWYdDYOg0HrEppZ2-j-Y_8H1gOe9w</recordid><startdate>20170801</startdate><enddate>20170801</enddate><creator>Yamaki, Susumu</creator><creator>Koga, Yuji</creator><creator>Nagashima, Akira</creator><creator>Kondo, Mitsuhiro</creator><creator>Shimada, Yoshiaki</creator><creator>Kadono, Keitaro</creator><creator>Moritomo, Ayako</creator><creator>Yoshihara, Kosei</creator><general>Elsevier Ltd</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></search><sort><creationdate>20170801</creationdate><title>Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition</title><author>Yamaki, Susumu ; Koga, Yuji ; Nagashima, Akira ; Kondo, Mitsuhiro ; Shimada, Yoshiaki ; Kadono, Keitaro ; Moritomo, Ayako ; Yoshihara, Kosei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-d6737add37715040aec3cd5dbb1fa7d0979f5114671fedf12b1eaa715050987b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Amine Oxidase (Copper-Containing) - antagonists & inhibitors</topic><topic>Animals</topic><topic>Cell Adhesion Molecules - antagonists & inhibitors</topic><topic>CYP2C19</topic><topic>CYP3A4</topic><topic>Cytochrome P-450 CYP2C19 Inhibitors - pharmacology</topic><topic>Cytochrome P-450 CYP3A Inhibitors - pharmacology</topic><topic>Diabetic Nephropathies - drug therapy</topic><topic>Diabetic nephropathy</topic><topic>Glycine - analogs & derivatives</topic><topic>Glycine - chemical synthesis</topic><topic>Glycine - chemistry</topic><topic>Glycine - pharmacology</topic><topic>Glycine - therapeutic use</topic><topic>Glycine amide</topic><topic>Humans</topic><topic>Molecular Docking Simulation</topic><topic>Proton Magnetic Resonance Spectroscopy</topic><topic>Rats</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>Vascular adhesion protein-1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yamaki, Susumu</creatorcontrib><creatorcontrib>Koga, Yuji</creatorcontrib><creatorcontrib>Nagashima, Akira</creatorcontrib><creatorcontrib>Kondo, Mitsuhiro</creatorcontrib><creatorcontrib>Shimada, Yoshiaki</creatorcontrib><creatorcontrib>Kadono, Keitaro</creatorcontrib><creatorcontrib>Moritomo, Ayako</creatorcontrib><creatorcontrib>Yoshihara, Kosei</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>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yamaki, Susumu</au><au>Koga, Yuji</au><au>Nagashima, Akira</au><au>Kondo, Mitsuhiro</au><au>Shimada, Yoshiaki</au><au>Kadono, Keitaro</au><au>Moritomo, Ayako</au><au>Yoshihara, Kosei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2017-08-01</date><risdate>2017</risdate><volume>25</volume><issue>15</issue><spage>4110</spage><epage>4122</epage><pages>4110-4122</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Vascular adhesion protein-1 (VAP-1) is a promising therapeutic target for the treatment of diabetic nephropathy. Here, we conducted optimization studies of our lead compound 1, which we previously reported as a novel VAP-1 inhibitor, to enhance the inhibition of human VAP-1 and to reduce CYP3A4 and CYP2C19 inhibition. As a result, we identified 3-chloro-4-{4-[5-(3-{[glycyl(methyl)amino]methyl}phenyl)pyrimidin-2-yl]piperazin-1-yl}benzoic acid (17h) as a novel orally active VAP-1 inhibitor, with 14-fold increased human VAP-1 inhibitory activity compared to 1, without CYP3A4 and CYP2C19 inhibition. Oral administration of 17h significantly inhibited the progression of proteinuria in streptozotocin (STZ) induced diabetic rats at 0.3 and 1mg/kg, suggesting that this compound has potential to be a therapeutic agent for the treatment of diabetic nephropathy.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28601507</pmid><doi>10.1016/j.bmc.2017.05.059</doi><tpages>13</tpages></addata></record> |
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| subjects | Amine Oxidase (Copper-Containing) - antagonists & inhibitors Animals Cell Adhesion Molecules - antagonists & inhibitors CYP2C19 CYP3A4 Cytochrome P-450 CYP2C19 Inhibitors - pharmacology Cytochrome P-450 CYP3A Inhibitors - pharmacology Diabetic Nephropathies - drug therapy Diabetic nephropathy Glycine - analogs & derivatives Glycine - chemical synthesis Glycine - chemistry Glycine - pharmacology Glycine - therapeutic use Glycine amide Humans Molecular Docking Simulation Proton Magnetic Resonance Spectroscopy Rats Spectrometry, Mass, Electrospray Ionization Vascular adhesion protein-1 |
| title | Synthesis and pharmacological evaluation of glycine amide derivatives as novel vascular adhesion protein-1 inhibitors without CYP3A4 and CYP2C19 inhibition |
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