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Discovery and Optimization of Piperidyl-1,2,3-Triazole Ureas as Potent, Selective, and in Vivo-Active Inhibitors of α/β-Hydrolase Domain Containing 6 (ABHD6)
α/β-Hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and func...
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| Published in: | Journal of medicinal chemistry 2013-11, Vol.56 (21), p.8270-8279 |
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| Main Authors: | , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a405t-85cc981c15e78c1a43e943901f337724888688eca28feeeba3c17234fa1491373 |
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| cites | cdi_FETCH-LOGICAL-a405t-85cc981c15e78c1a43e943901f337724888688eca28feeeba3c17234fa1491373 |
| container_end_page | 8279 |
| container_issue | 21 |
| container_start_page | 8270 |
| container_title | Journal of medicinal chemistry |
| container_volume | 56 |
| creator | Hsu, Ku-Lung Tsuboi, Katsunori Chang, Jae Won Whitby, Landon R Speers, Anna E Pugh, Holly Cravatt, Benjamin F |
| description | α/β-Hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells ( |
| doi_str_mv | 10.1021/jm400899c |
| format | article |
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The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells (<5 nM) and, at equivalent doses in mice (1 mg kg–1), act as systemic and peripherally restricted ABHD6 inhibitors, respectively. We also describe an orally bioavailable ABHD6 inhibitor, KT185, that displays excellent selectivity against other brain and liver serine hydrolases in vivo. 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Med. Chem</addtitle><description>α/β-Hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells (<5 nM) and, at equivalent doses in mice (1 mg kg–1), act as systemic and peripherally restricted ABHD6 inhibitors, respectively. We also describe an orally bioavailable ABHD6 inhibitor, KT185, that displays excellent selectivity against other brain and liver serine hydrolases in vivo. We thus describe several chemical probes for biological studies of ABHD6, including brain-penetrant and peripherally restricted inhibitors that should prove of value for interrogating ABHD6 function in animal models.</description><subject>Animals</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Mice</subject><subject>Models, Animal</subject><subject>Molecular Structure</subject><subject>Monoacylglycerol Lipases - antagonists & inhibitors</subject><subject>Monoacylglycerol Lipases - metabolism</subject><subject>Piperidines - chemistry</subject><subject>Piperidines - metabolism</subject><subject>Piperidines - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Triazoles - chemistry</subject><subject>Triazoles - metabolism</subject><subject>Triazoles - pharmacology</subject><subject>Urea - analogs & derivatives</subject><subject>Urea - chemistry</subject><subject>Urea - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNptkd9KHDEUh0NpqVvbi75AyU2hwkbzb2aSm8J213YFQaHq7ZDNntEsM8mSjAvry_gM-iA-U6Ori0LhwIGT73zh8EPoK6P7jHJ2sOgkpUpr-w4NWMEpkYrK92hAKeeEl1zsoE8pLSilgnHxEe1wmTGuiwG6nbhkwwriGhs_xyfL3nXuxvQueBwafOqWEN183RI25ENBzqIzN6EFfB7BJJzrNPTg-yH-Cy3Y3q1g-CRyHl-4VSCjpxk-8ldu5voQ06P14e7g4Z5M1_MYWpMAT0Jn8sI4-D535y9xiX-Mfk0n5d5n9KExbYIvz30Xnf8-PBtPyfHJn6Px6JgYSYueqMJarZhlBVTKMiMFaCk0ZY0QVcWlUqpUCqzhqgGAmRGWVVzIxjCpmajELvq58S6vZx3Mbb4pmrZeRteZuK6DcfXbF--u6suwqoVWlSp1FuxtBDaGlCI0211G68eU6m1Kmf32-rMt-RJLBr5vAGNTvQjX0efb_yP6BwHHmxc</recordid><startdate>20131114</startdate><enddate>20131114</enddate><creator>Hsu, Ku-Lung</creator><creator>Tsuboi, Katsunori</creator><creator>Chang, Jae Won</creator><creator>Whitby, Landon R</creator><creator>Speers, Anna E</creator><creator>Pugh, Holly</creator><creator>Cravatt, Benjamin F</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>5PM</scope></search><sort><creationdate>20131114</creationdate><title>Discovery and Optimization of Piperidyl-1,2,3-Triazole Ureas as Potent, Selective, and in Vivo-Active Inhibitors of α/β-Hydrolase Domain Containing 6 (ABHD6)</title><author>Hsu, Ku-Lung ; Tsuboi, Katsunori ; Chang, Jae Won ; Whitby, Landon R ; Speers, Anna E ; Pugh, Holly ; Cravatt, Benjamin F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a405t-85cc981c15e78c1a43e943901f337724888688eca28feeeba3c17234fa1491373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Mice</topic><topic>Models, Animal</topic><topic>Molecular Structure</topic><topic>Monoacylglycerol Lipases - antagonists & inhibitors</topic><topic>Monoacylglycerol Lipases - metabolism</topic><topic>Piperidines - chemistry</topic><topic>Piperidines - metabolism</topic><topic>Piperidines - pharmacology</topic><topic>Structure-Activity Relationship</topic><topic>Triazoles - chemistry</topic><topic>Triazoles - metabolism</topic><topic>Triazoles - pharmacology</topic><topic>Urea - analogs & derivatives</topic><topic>Urea - chemistry</topic><topic>Urea - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hsu, Ku-Lung</creatorcontrib><creatorcontrib>Tsuboi, Katsunori</creatorcontrib><creatorcontrib>Chang, Jae Won</creatorcontrib><creatorcontrib>Whitby, Landon R</creatorcontrib><creatorcontrib>Speers, Anna E</creatorcontrib><creatorcontrib>Pugh, Holly</creatorcontrib><creatorcontrib>Cravatt, Benjamin F</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hsu, Ku-Lung</au><au>Tsuboi, Katsunori</au><au>Chang, Jae Won</au><au>Whitby, Landon R</au><au>Speers, Anna E</au><au>Pugh, Holly</au><au>Cravatt, Benjamin F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and Optimization of Piperidyl-1,2,3-Triazole Ureas as Potent, Selective, and in Vivo-Active Inhibitors of α/β-Hydrolase Domain Containing 6 (ABHD6)</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-11-14</date><risdate>2013</risdate><volume>56</volume><issue>21</issue><spage>8270</spage><epage>8279</epage><pages>8270-8279</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>α/β-Hydrolase domain containing 6 (ABHD6) is a transmembrane serine hydrolase that hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) to regulate certain forms of cannabinoid receptor-dependent signaling in the nervous system. The full spectrum of ABHD6 metabolic activities and functions is currently unknown and would benefit from selective, in vivo-active inhibitors. Here, we report the development and characterization of an advanced series of irreversible (2-substituted)-piperidyl-1,2,3-triazole urea inhibitors of ABHD6, including compounds KT182 and KT203, which show exceptional potency and selectivity in cells (<5 nM) and, at equivalent doses in mice (1 mg kg–1), act as systemic and peripherally restricted ABHD6 inhibitors, respectively. We also describe an orally bioavailable ABHD6 inhibitor, KT185, that displays excellent selectivity against other brain and liver serine hydrolases in vivo. We thus describe several chemical probes for biological studies of ABHD6, including brain-penetrant and peripherally restricted inhibitors that should prove of value for interrogating ABHD6 function in animal models.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24152295</pmid><doi>10.1021/jm400899c</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2013-11, Vol.56 (21), p.8270-8279 |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3987869 |
| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Animals Dose-Response Relationship, Drug Drug Discovery Enzyme Inhibitors - chemistry Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Humans Mice Models, Animal Molecular Structure Monoacylglycerol Lipases - antagonists & inhibitors Monoacylglycerol Lipases - metabolism Piperidines - chemistry Piperidines - metabolism Piperidines - pharmacology Structure-Activity Relationship Triazoles - chemistry Triazoles - metabolism Triazoles - pharmacology Urea - analogs & derivatives Urea - chemistry Urea - pharmacology |
| title | Discovery and Optimization of Piperidyl-1,2,3-Triazole Ureas as Potent, Selective, and in Vivo-Active Inhibitors of α/β-Hydrolase Domain Containing 6 (ABHD6) |
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