Discovery of 2‑(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (Perampanel): A Novel, Noncompetitive α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonist
Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate recept...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-12, Vol.55 (23), p.10584-10600 |
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| container_issue | 23 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 55 |
| creator | Hibi, Shigeki Ueno, Koshi Nagato, Satoshi Kawano, Koki Ito, Koichi Norimine, Yoshihiko Takenaka, Osamu Hanada, Takahisa Yonaga, Masahiro |
| description | Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate receptors. The structure–activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca2+ influx assay (IC50 = 60 nM) and in an in vivo AMPA-induced seizure model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy. |
| doi_str_mv | 10.1021/jm301268u |
| format | Article |
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Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm301268u</identifier><identifier>PMID: 23181587</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Biological Availability ; Drug Discovery ; Half-Life ; High-Throughput Screening Assays ; In Vitro Techniques ; Magnetic Resonance Spectroscopy ; Male ; Mice ; Pyridones - chemistry ; Pyridones - pharmacokinetics ; Pyridones - pharmacology ; Rats ; Receptors, AMPA - antagonists & inhibitors ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2012-12, Vol.55 (23), p.10584-10600</ispartof><rights>Copyright © 2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-cb2505f3b60d40bf05acc25167fd23f4a34a2db7cab4c22b7cfa24248a7a12643</citedby><cites>FETCH-LOGICAL-a315t-cb2505f3b60d40bf05acc25167fd23f4a34a2db7cab4c22b7cfa24248a7a12643</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm301268u$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm301268u$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23181587$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hibi, Shigeki</creatorcontrib><creatorcontrib>Ueno, Koshi</creatorcontrib><creatorcontrib>Nagato, Satoshi</creatorcontrib><creatorcontrib>Kawano, Koki</creatorcontrib><creatorcontrib>Ito, Koichi</creatorcontrib><creatorcontrib>Norimine, Yoshihiko</creatorcontrib><creatorcontrib>Takenaka, Osamu</creatorcontrib><creatorcontrib>Hanada, Takahisa</creatorcontrib><creatorcontrib>Yonaga, Masahiro</creatorcontrib><title>Discovery of 2‑(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (Perampanel): A Novel, Noncompetitive α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonist</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Dysfunction of glutamatergic neurotransmission has been implicated in the pathogenesis of epilepsy and numerous other neurological diseases. Here we describe the discovery of a series of 1,3,5-triaryl-1H-pyridin-2-one derivatives as noncompetitive antagonists of AMPA-type ionotropic glutamate receptors. The structure–activity relationships for this series of compounds were investigated by manipulating individual aromatic rings located at positions 1, 3, and 5 of the pyridone ring. This culminated in the discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (perampanel, 6), a novel, noncompetitive AMPA receptor antagonist that showed potent activity in an in vitro AMPA-induced Ca2+ influx assay (IC50 = 60 nM) and in an in vivo AMPA-induced seizure model (minimum effective dose of 2 mg/kg po). Perampanel is currently in regulatory submission for partial-onset seizures associated with epilepsy.</description><subject>Animals</subject><subject>Biological Availability</subject><subject>Drug Discovery</subject><subject>Half-Life</subject><subject>High-Throughput Screening Assays</subject><subject>In Vitro Techniques</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Mice</subject><subject>Pyridones - chemistry</subject><subject>Pyridones - pharmacokinetics</subject><subject>Pyridones - pharmacology</subject><subject>Rats</subject><subject>Receptors, AMPA - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU1uFDEQhS0EIkNgwQWQN0gzUgx22f0Du1b4lQKJEKxbbreb8ajb7tg90XRWuUKOwkHgEJyEgkmyYlV26el9VfUIeSr4C8FBvNwMkgvIy-09shAZcKZKru6TBecADHKQB-RRShvOuRQgH5IDkKIUWVksyM83LplwYeNMQ0fh99X1EtjpLjDBxrX1c88yNs7Rtc4zYPgVR8Bat57bGG77EvurxvrL4N0UXW_p8sxGPYza2371mlb0MxL6IyzehGG0k5vchaW_fiCuGpwPaPHPcTcjbrDTGkGKuRR2-jL0dkSW9sEZWhnX0mX16axa0S_W2HEKkVZ-0t-RnabH5EGn-2Sf3NRD8u3d26_HH9jJ6fuPx9UJ01JkEzMNZDzrZJPzVvGm45k2BjKRF10LslNaKg1tUxjdKAOAj06DAlXqQuOdlTwky70vTna-tWmqBzyj7XvcOGxTjVd-xXOuRIHS1V5qYkgp2q4eoxt0nGvB67_p1XfpofbZje22GWx7p7yNCwXP9wJtUr0J2-hxy_8Y_QF0oqS1</recordid><startdate>20121213</startdate><enddate>20121213</enddate><creator>Hibi, Shigeki</creator><creator>Ueno, Koshi</creator><creator>Nagato, Satoshi</creator><creator>Kawano, Koki</creator><creator>Ito, Koichi</creator><creator>Norimine, Yoshihiko</creator><creator>Takenaka, Osamu</creator><creator>Hanada, Takahisa</creator><creator>Yonaga, Masahiro</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>7X8</scope></search><sort><creationdate>20121213</creationdate><title>Discovery of 2‑(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (Perampanel): A Novel, Noncompetitive α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonist</title><author>Hibi, Shigeki ; Ueno, Koshi ; Nagato, Satoshi ; Kawano, Koki ; Ito, Koichi ; Norimine, Yoshihiko ; Takenaka, Osamu ; Hanada, Takahisa ; Yonaga, Masahiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-cb2505f3b60d40bf05acc25167fd23f4a34a2db7cab4c22b7cfa24248a7a12643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Biological Availability</topic><topic>Drug Discovery</topic><topic>Half-Life</topic><topic>High-Throughput Screening Assays</topic><topic>In Vitro Techniques</topic><topic>Magnetic Resonance Spectroscopy</topic><topic>Male</topic><topic>Mice</topic><topic>Pyridones - chemistry</topic><topic>Pyridones - pharmacokinetics</topic><topic>Pyridones - pharmacology</topic><topic>Rats</topic><topic>Receptors, AMPA - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hibi, Shigeki</creatorcontrib><creatorcontrib>Ueno, Koshi</creatorcontrib><creatorcontrib>Nagato, Satoshi</creatorcontrib><creatorcontrib>Kawano, Koki</creatorcontrib><creatorcontrib>Ito, Koichi</creatorcontrib><creatorcontrib>Norimine, Yoshihiko</creatorcontrib><creatorcontrib>Takenaka, Osamu</creatorcontrib><creatorcontrib>Hanada, Takahisa</creatorcontrib><creatorcontrib>Yonaga, Masahiro</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hibi, Shigeki</au><au>Ueno, Koshi</au><au>Nagato, Satoshi</au><au>Kawano, Koki</au><au>Ito, Koichi</au><au>Norimine, Yoshihiko</au><au>Takenaka, Osamu</au><au>Hanada, Takahisa</au><au>Yonaga, Masahiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 2‑(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (Perampanel): A Novel, Noncompetitive α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonist</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. 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| ispartof | Journal of medicinal chemistry, 2012-12, Vol.55 (23), p.10584-10600 |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Biological Availability Drug Discovery Half-Life High-Throughput Screening Assays In Vitro Techniques Magnetic Resonance Spectroscopy Male Mice Pyridones - chemistry Pyridones - pharmacokinetics Pyridones - pharmacology Rats Receptors, AMPA - antagonists & inhibitors Structure-Activity Relationship |
| title | Discovery of 2‑(2-Oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile (Perampanel): A Novel, Noncompetitive α‑Amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonist |
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