Elucidating the mechanism of cytochrome P450-mediated pyrimidine ring conversion to pyrazole metabolites with the BACE1 inhibitor GNE-892 in rats
We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed...
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| Veröffentlicht in: | Drug metabolism and disposition 2014-05, Vol.42 (5), p.890-898 |
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| creator | Takahashi, Ryan Ma, Shuguang Deese, Alan Yue, Qin Kim-Kang, Heasook Yi, Yijun Siu, Michael Hunt, Kevin W Kallan, Nicholas C Hop, Cornelis E C A Liu, Xingrong Khojasteh, S Cyrus |
| description | We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for |
| doi_str_mv | 10.1124/dmd.114.057141 |
| format | Article |
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Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.</description><identifier>ISSN: 0090-9556</identifier><identifier>EISSN: 1521-009X</identifier><identifier>DOI: 10.1124/dmd.114.057141</identifier><identifier>PMID: 24595682</identifier><language>eng</language><publisher>United States</publisher><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Animals ; Aryl Hydrocarbon Hydroxylases - metabolism ; Aspartic Acid Endopeptidases - antagonists & inhibitors ; Bile - metabolism ; Biotransformation ; Cells, Cultured ; Chromatography, High Pressure Liquid ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - urine ; Feces - chemistry ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Imidazoles - metabolism ; Imidazoles - pharmacokinetics ; Imidazoles - urine ; Male ; Pyrazoles - metabolism ; Pyrimidines - metabolism ; Rats ; Rats, Sprague-Dawley ; Spiro Compounds - metabolism ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - urine ; Tandem Mass Spectrometry</subject><ispartof>Drug metabolism and disposition, 2014-05, Vol.42 (5), p.890-898</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c258t-80e31a6b84fe59f26300802134306f18c51428d0ad759f53b89a23499f40afde3</citedby><cites>FETCH-LOGICAL-c258t-80e31a6b84fe59f26300802134306f18c51428d0ad759f53b89a23499f40afde3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24595682$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takahashi, Ryan</creatorcontrib><creatorcontrib>Ma, Shuguang</creatorcontrib><creatorcontrib>Deese, Alan</creatorcontrib><creatorcontrib>Yue, Qin</creatorcontrib><creatorcontrib>Kim-Kang, Heasook</creatorcontrib><creatorcontrib>Yi, Yijun</creatorcontrib><creatorcontrib>Siu, Michael</creatorcontrib><creatorcontrib>Hunt, Kevin W</creatorcontrib><creatorcontrib>Kallan, Nicholas C</creatorcontrib><creatorcontrib>Hop, Cornelis E C A</creatorcontrib><creatorcontrib>Liu, Xingrong</creatorcontrib><creatorcontrib>Khojasteh, S Cyrus</creatorcontrib><title>Elucidating the mechanism of cytochrome P450-mediated pyrimidine ring conversion to pyrazole metabolites with the BACE1 inhibitor GNE-892 in rats</title><title>Drug metabolism and disposition</title><addtitle>Drug Metab Dispos</addtitle><description>We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.</description><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Animals</subject><subject>Aryl Hydrocarbon Hydroxylases - metabolism</subject><subject>Aspartic Acid Endopeptidases - antagonists & inhibitors</subject><subject>Bile - metabolism</subject><subject>Biotransformation</subject><subject>Cells, Cultured</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - urine</subject><subject>Feces - chemistry</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - enzymology</subject><subject>Imidazoles - metabolism</subject><subject>Imidazoles - pharmacokinetics</subject><subject>Imidazoles - urine</subject><subject>Male</subject><subject>Pyrazoles - metabolism</subject><subject>Pyrimidines - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Spiro Compounds - metabolism</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - urine</subject><subject>Tandem Mass Spectrometry</subject><issn>0090-9556</issn><issn>1521-009X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUU1PGzEQtSpQCbTXHpGPXDYdf23sI0QBKkWFQyv1tvLa3q7R7jq1HVD4F_xjnIZy7emN5n2MNA-hLwTmhFD-1Y62DHwOYkE4-YBmRFBSAahfR2hWAColRH2CTlN6ACCcM_URnVAulKglnaGX1bA13ursp9849w6PzvR68mnEocNml4PpYxgdvucCqtFZr7OzeLOLfvTWTw7HvdOE6dHF5MOEc9iz-jkM-7Cs2zD47BJ-8rn_e-Hqcrki2E-9b30OEd98X1VS0bLBUef0CR13ekju8xueoZ_Xqx_L22p9d_NtebmuDBUyVxIcI7puJe-cUB2tGYAEShhnUHdEGkE4lRa0XRRasFYqTRlXquOgO-vYGbo45G5i-LN1KTejT8YNg55c2KaG1IqrhaQM_i8VhIGgslZFOj9ITQwpRdc1m_IpHXcNgWbfWFMaKwNvDo0Vw_lb9rYt732X_6uIvQIkKpEp</recordid><startdate>201405</startdate><enddate>201405</enddate><creator>Takahashi, Ryan</creator><creator>Ma, Shuguang</creator><creator>Deese, Alan</creator><creator>Yue, Qin</creator><creator>Kim-Kang, Heasook</creator><creator>Yi, Yijun</creator><creator>Siu, Michael</creator><creator>Hunt, Kevin W</creator><creator>Kallan, Nicholas C</creator><creator>Hop, Cornelis E C A</creator><creator>Liu, Xingrong</creator><creator>Khojasteh, S Cyrus</creator><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>7U7</scope><scope>C1K</scope></search><sort><creationdate>201405</creationdate><title>Elucidating the mechanism of cytochrome P450-mediated pyrimidine ring conversion to pyrazole metabolites with the BACE1 inhibitor GNE-892 in rats</title><author>Takahashi, Ryan ; Ma, Shuguang ; Deese, Alan ; Yue, Qin ; Kim-Kang, Heasook ; Yi, Yijun ; Siu, Michael ; Hunt, Kevin W ; Kallan, Nicholas C ; Hop, Cornelis E C A ; Liu, Xingrong ; Khojasteh, S Cyrus</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c258t-80e31a6b84fe59f26300802134306f18c51428d0ad759f53b89a23499f40afde3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Animals</topic><topic>Aryl Hydrocarbon Hydroxylases - metabolism</topic><topic>Aspartic Acid Endopeptidases - antagonists & inhibitors</topic><topic>Bile - metabolism</topic><topic>Biotransformation</topic><topic>Cells, Cultured</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - urine</topic><topic>Feces - chemistry</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - enzymology</topic><topic>Imidazoles - metabolism</topic><topic>Imidazoles - pharmacokinetics</topic><topic>Imidazoles - urine</topic><topic>Male</topic><topic>Pyrazoles - metabolism</topic><topic>Pyrimidines - metabolism</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Spiro Compounds - metabolism</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - urine</topic><topic>Tandem Mass Spectrometry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takahashi, Ryan</creatorcontrib><creatorcontrib>Ma, Shuguang</creatorcontrib><creatorcontrib>Deese, Alan</creatorcontrib><creatorcontrib>Yue, Qin</creatorcontrib><creatorcontrib>Kim-Kang, Heasook</creatorcontrib><creatorcontrib>Yi, Yijun</creatorcontrib><creatorcontrib>Siu, Michael</creatorcontrib><creatorcontrib>Hunt, Kevin W</creatorcontrib><creatorcontrib>Kallan, Nicholas C</creatorcontrib><creatorcontrib>Hop, Cornelis E C A</creatorcontrib><creatorcontrib>Liu, Xingrong</creatorcontrib><creatorcontrib>Khojasteh, S Cyrus</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>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Drug metabolism and disposition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takahashi, Ryan</au><au>Ma, Shuguang</au><au>Deese, Alan</au><au>Yue, Qin</au><au>Kim-Kang, Heasook</au><au>Yi, Yijun</au><au>Siu, Michael</au><au>Hunt, Kevin W</au><au>Kallan, Nicholas C</au><au>Hop, Cornelis E C A</au><au>Liu, Xingrong</au><au>Khojasteh, S Cyrus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Elucidating the mechanism of cytochrome P450-mediated pyrimidine ring conversion to pyrazole metabolites with the BACE1 inhibitor GNE-892 in rats</atitle><jtitle>Drug metabolism and disposition</jtitle><addtitle>Drug Metab Dispos</addtitle><date>2014-05</date><risdate>2014</risdate><volume>42</volume><issue>5</issue><spage>890</spage><epage>898</epage><pages>890-898</pages><issn>0090-9556</issn><eissn>1521-009X</eissn><abstract>We investigated an uncommon biotransformation of pyrimidine during the metabolism of GNE-892 ((R)-2-amino-1,3',3'-trimethyl-7'-(pyrimidin-5-yl)-3',4'-dihydro-2'H-spiro[imidazole-4,1'-naphthalen]-5(1H)-one), a β-secretase 1 inhibitor. Three novel metabolites, formed by conversion of pyrimidine to pyrazole, were observed in the (14)C-radiolabeled mass balance study in rats. Their structures were characterized by high-resolution mass spectrometry and nuclear magnetic resonance. Although these metabolites accounted for <5% of the administered dose, their unique nature prompted us to conduct further investigations. The pyrazole-containing metabolites were formed in vitro with rat hepatocytes and liver microsomes, which supported that they were formed during hepatic metabolism. Further, their generation was inhibited by 1-aminobenzotriazole, indicating involvement of cytochrome P450s. Studies with rat recombinant enzymes identified that CYP2D2 generated the N-hydroxypyrazole metabolite from GNE-892. This biotransformation proceeded through multiple steps from the likely precursor, pyrimidine N-oxide. On the basis of these data, we propose a mechanism in which the pyrimidine is activated via N-oxidation, followed by a second oxidative process that opens the pyrimidine ring to form a formamide intermediate. After hydrolysis of the formamide, a carbon is lost as formic acid, together with ring closure to form the pyrazole ring. This article highlights a mechanistic approach for determining the biotransformation of the pyrimidine to a pyrazole for GNE-892.</abstract><cop>United States</cop><pmid>24595682</pmid><doi>10.1124/dmd.114.057141</doi><tpages>9</tpages></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Amyloid Precursor Protein Secretases - antagonists & inhibitors Animals Aryl Hydrocarbon Hydroxylases - metabolism Aspartic Acid Endopeptidases - antagonists & inhibitors Bile - metabolism Biotransformation Cells, Cultured Chromatography, High Pressure Liquid Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - urine Feces - chemistry Hepatocytes - drug effects Hepatocytes - enzymology Imidazoles - metabolism Imidazoles - pharmacokinetics Imidazoles - urine Male Pyrazoles - metabolism Pyrimidines - metabolism Rats Rats, Sprague-Dawley Spiro Compounds - metabolism Spiro Compounds - pharmacokinetics Spiro Compounds - urine Tandem Mass Spectrometry |
| title | Elucidating the mechanism of cytochrome P450-mediated pyrimidine ring conversion to pyrazole metabolites with the BACE1 inhibitor GNE-892 in rats |
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