Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6
The elongase of long chain fatty acids family 6 (ELOVL6) is a rate-limiting enzyme for the elongation of saturated and monounsaturated long chain fatty acids. ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 def...
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| Veröffentlicht in: | European journal of pharmacology 2010-03, Vol.630 (1), p.34-41 |
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| creator | Shimamura, Ken Nagumo, Akira Miyamoto, Yasuhisa Kitazawa, Hidefumi Kanesaka, Maki Yoshimoto, Ryo Aragane, Katsumi Morita, Naomi Ohe, Tomoyuki Takahashi, Toshiyuki Nagase, Tsuyoshi Sato, Nagaaki Tokita, Shigeru |
| description | The elongase of long chain fatty acids family 6 (ELOVL6) is a rate-limiting enzyme for the elongation of saturated and monounsaturated long chain fatty acids. ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 deficient mice are protected from high-fat-diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes. We previously identified an indoledione compound, Compound A, as the first inhibitor for mammalian ELOVL6. In this study, we discovered a novel compound, Compound B, and characterized its biochemical and pharmacological properties. Compound B has a more appropriate profile for use as a pharmacological tool compared to Compound A. Chronic treatment with Compound B in model animals, diet-induced obesity (DIO) and KKAy mice, showed significant reduction in hepatic fatty acid composition, suggesting that it effectively inhibits ELOVL6 activity in the liver. However, no improvement in insulin resistance by ELOVL6 inhibition was found in these model animals. Further studies need to address the impact of ELOVL6 inhibition on pharmacological abnormalities in several model animals. This is the first report on pharmacology data from chronic studies using a selective ELOVL6 inhibitor. Compound B appears to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of ELOVL6 inhibitors. |
| doi_str_mv | 10.1016/j.ejphar.2009.12.033 |
| format | Article |
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ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 deficient mice are protected from high-fat-diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes. We previously identified an indoledione compound, Compound A, as the first inhibitor for mammalian ELOVL6. In this study, we discovered a novel compound, Compound B, and characterized its biochemical and pharmacological properties. Compound B has a more appropriate profile for use as a pharmacological tool compared to Compound A. Chronic treatment with Compound B in model animals, diet-induced obesity (DIO) and KKAy mice, showed significant reduction in hepatic fatty acid composition, suggesting that it effectively inhibits ELOVL6 activity in the liver. However, no improvement in insulin resistance by ELOVL6 inhibition was found in these model animals. Further studies need to address the impact of ELOVL6 inhibition on pharmacological abnormalities in several model animals. This is the first report on pharmacology data from chronic studies using a selective ELOVL6 inhibitor. Compound B appears to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of ELOVL6 inhibitors.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2009.12.033</identifier><identifier>PMID: 20045404</identifier><identifier>CODEN: EJPHAZ</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Acetyltransferases - antagonists & inhibitors ; Acetyltransferases - chemistry ; Administration, Oral ; Animals ; Biological and medical sciences ; Cell Line, Tumor ; Diabetes ; Diabetes. 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ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 deficient mice are protected from high-fat-diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes. We previously identified an indoledione compound, Compound A, as the first inhibitor for mammalian ELOVL6. In this study, we discovered a novel compound, Compound B, and characterized its biochemical and pharmacological properties. Compound B has a more appropriate profile for use as a pharmacological tool compared to Compound A. Chronic treatment with Compound B in model animals, diet-induced obesity (DIO) and KKAy mice, showed significant reduction in hepatic fatty acid composition, suggesting that it effectively inhibits ELOVL6 activity in the liver. However, no improvement in insulin resistance by ELOVL6 inhibition was found in these model animals. Further studies need to address the impact of ELOVL6 inhibition on pharmacological abnormalities in several model animals. This is the first report on pharmacology data from chronic studies using a selective ELOVL6 inhibitor. Compound B appears to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of ELOVL6 inhibitors.</description><subject>Acetyltransferases - antagonists & inhibitors</subject><subject>Acetyltransferases - chemistry</subject><subject>Administration, Oral</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drugs, Investigational - chemistry</subject><subject>Drugs, Investigational - pharmacology</subject><subject>Elovl</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Fatty Acids - metabolism</subject><subject>Inhibitor</subject><subject>Inhibitory Concentration 50</subject><subject>Liver - drug effects</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred Strains</subject><subject>Molecular Structure</subject><subject>Pharmacology. Drug treatments</subject><subject>Sensitivity and Specificity</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1v1DAQhi1ERZfCP0AoF8SFhPFHNs0FqSqFVlqpF-BqTeyx6pUTL3Z2pfLr6yUL3DiMLI2edzzzMPaGQ8OBrz9uG9ruHjA1AqBvuGhAymdsxS-7voaOi-dsBcBVLfq-P2cvc94CQNuL9gU7LxHVKlArFj77bOKB0mOFk61MGYhmpuR_4ezjVEVXYTUVIFS7ONM0f6gyBTKzP9DvREwYQgkvHT89-MHPMVWu1IjjiMHjVN1s7n9s1q_YmcOQ6fXpvWDfv9x8u76tN_df766vNrVRspvrgbAzxilpZY_lEkBpLIh1N3DrzACDa53rHXBhcA1m4NxK0UoYerJWOS4v2Ptl7i7Fn3vKsx7LlRQCThT3WXdStm2n4LKQaiFNijkncnqX_IjpUXPQR816qxfN-qhZc6GL5hJ7e_pgP4xk_4b-eC3AuxOA2WBwCSfj8z9OqO64ceE-LRwVHQdPSWfjaTJkfSqStY3-_5s8AeefnsU</recordid><startdate>20100325</startdate><enddate>20100325</enddate><creator>Shimamura, Ken</creator><creator>Nagumo, Akira</creator><creator>Miyamoto, Yasuhisa</creator><creator>Kitazawa, Hidefumi</creator><creator>Kanesaka, Maki</creator><creator>Yoshimoto, Ryo</creator><creator>Aragane, Katsumi</creator><creator>Morita, Naomi</creator><creator>Ohe, Tomoyuki</creator><creator>Takahashi, Toshiyuki</creator><creator>Nagase, Tsuyoshi</creator><creator>Sato, Nagaaki</creator><creator>Tokita, Shigeru</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>IQODW</scope><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>20100325</creationdate><title>Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6</title><author>Shimamura, Ken ; Nagumo, Akira ; Miyamoto, Yasuhisa ; Kitazawa, Hidefumi ; Kanesaka, Maki ; Yoshimoto, Ryo ; Aragane, Katsumi ; Morita, Naomi ; Ohe, Tomoyuki ; Takahashi, Toshiyuki ; Nagase, Tsuyoshi ; Sato, Nagaaki ; Tokita, Shigeru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c437t-bea7ccf43d39a7120a3cd0267b1dfcb0bf5ff9f012ca60cb11d32530b9edd4f13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Acetyltransferases - antagonists & inhibitors</topic><topic>Acetyltransferases - chemistry</topic><topic>Administration, Oral</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Diabetes</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drugs, Investigational - chemistry</topic><topic>Drugs, Investigational - pharmacology</topic><topic>Elovl</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Fatty Acids - metabolism</topic><topic>Inhibitor</topic><topic>Inhibitory Concentration 50</topic><topic>Liver - drug effects</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred Strains</topic><topic>Molecular Structure</topic><topic>Pharmacology. Drug treatments</topic><topic>Sensitivity and Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shimamura, Ken</creatorcontrib><creatorcontrib>Nagumo, Akira</creatorcontrib><creatorcontrib>Miyamoto, Yasuhisa</creatorcontrib><creatorcontrib>Kitazawa, Hidefumi</creatorcontrib><creatorcontrib>Kanesaka, Maki</creatorcontrib><creatorcontrib>Yoshimoto, Ryo</creatorcontrib><creatorcontrib>Aragane, Katsumi</creatorcontrib><creatorcontrib>Morita, Naomi</creatorcontrib><creatorcontrib>Ohe, Tomoyuki</creatorcontrib><creatorcontrib>Takahashi, Toshiyuki</creatorcontrib><creatorcontrib>Nagase, Tsuyoshi</creatorcontrib><creatorcontrib>Sato, Nagaaki</creatorcontrib><creatorcontrib>Tokita, Shigeru</creatorcontrib><collection>Pascal-Francis</collection><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>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shimamura, Ken</au><au>Nagumo, Akira</au><au>Miyamoto, Yasuhisa</au><au>Kitazawa, Hidefumi</au><au>Kanesaka, Maki</au><au>Yoshimoto, Ryo</au><au>Aragane, Katsumi</au><au>Morita, Naomi</au><au>Ohe, Tomoyuki</au><au>Takahashi, Toshiyuki</au><au>Nagase, Tsuyoshi</au><au>Sato, Nagaaki</au><au>Tokita, Shigeru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2010-03-25</date><risdate>2010</risdate><volume>630</volume><issue>1</issue><spage>34</spage><epage>41</epage><pages>34-41</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><coden>EJPHAZ</coden><abstract>The elongase of long chain fatty acids family 6 (ELOVL6) is a rate-limiting enzyme for the elongation of saturated and monounsaturated long chain fatty acids. ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 deficient mice are protected from high-fat-diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes. We previously identified an indoledione compound, Compound A, as the first inhibitor for mammalian ELOVL6. In this study, we discovered a novel compound, Compound B, and characterized its biochemical and pharmacological properties. Compound B has a more appropriate profile for use as a pharmacological tool compared to Compound A. Chronic treatment with Compound B in model animals, diet-induced obesity (DIO) and KKAy mice, showed significant reduction in hepatic fatty acid composition, suggesting that it effectively inhibits ELOVL6 activity in the liver. However, no improvement in insulin resistance by ELOVL6 inhibition was found in these model animals. Further studies need to address the impact of ELOVL6 inhibition on pharmacological abnormalities in several model animals. This is the first report on pharmacology data from chronic studies using a selective ELOVL6 inhibitor. Compound B appears to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of ELOVL6 inhibitors.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>20045404</pmid><doi>10.1016/j.ejphar.2009.12.033</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Acetyltransferases - antagonists & inhibitors Acetyltransferases - chemistry Administration, Oral Animals Biological and medical sciences Cell Line, Tumor Diabetes Diabetes. Impaired glucose tolerance Dose-Response Relationship, Drug Drug Discovery Drug Evaluation, Preclinical Drugs, Investigational - chemistry Drugs, Investigational - pharmacology Elovl Endocrine pancreas. Apud cells (diseases) Endocrinopathies Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Etiopathogenesis. Screening. Investigations. Target tissue resistance Fatty Acids - metabolism Inhibitor Inhibitory Concentration 50 Liver - drug effects Male Medical sciences Mice Mice, Inbred C57BL Mice, Inbred Strains Molecular Structure Pharmacology. Drug treatments Sensitivity and Specificity |
| title | Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6 |
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