Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists
We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3436-3451 |
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| container_title | Journal of medicinal chemistry |
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| creator | Saku, Osamu Ishida, Hiroshi Atsumi, Eri Sugimoto, Yoshiyuki Kodaira, Hiroshi Kato, Yoshimitsu Shirakura, Shiro Nakasato, Yoshisuke |
| description | We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood–brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury. |
| doi_str_mv | 10.1021/jm300101n |
| format | Article |
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In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood–brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm300101n</identifier><identifier>PMID: 22394104</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Alkadienes - chemical synthesis ; Alkadienes - pharmacokinetics ; Alkadienes - pharmacology ; Amides - chemical synthesis ; Amides - pharmacokinetics ; Amides - pharmacology ; Analgesics - chemical synthesis ; Analgesics - pharmacokinetics ; Analgesics - pharmacology ; Animals ; Blood-Brain Barrier - metabolism ; Calcium - metabolism ; Capsaicin - pharmacology ; Dogs ; Epstein-Barr Virus Nuclear Antigens - genetics ; Haplorhini ; HEK293 Cells ; Humans ; Hyperalgesia - prevention & control ; Male ; Microsomes, Liver - metabolism ; Neuralgia - prevention & control ; Quinolones - chemical synthesis ; Quinolones - pharmacokinetics ; Quinolones - pharmacology ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; Structure-Activity Relationship ; TRPV Cation Channels - agonists ; TRPV Cation Channels - antagonists & inhibitors ; TRPV Cation Channels - genetics</subject><ispartof>Journal of medicinal chemistry, 2012-04, Vol.55 (7), p.3436-3451</ispartof><rights>Copyright © 2012 American Chemical Society</rights><rights>2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-bd5982a70131bc5f6d915d9a9f96228c5781fec420293dccb216dbcd9b09353c3</citedby><cites>FETCH-LOGICAL-a315t-bd5982a70131bc5f6d915d9a9f96228c5781fec420293dccb216dbcd9b09353c3</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/jm300101n$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm300101n$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22394104$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Saku, Osamu</creatorcontrib><creatorcontrib>Ishida, Hiroshi</creatorcontrib><creatorcontrib>Atsumi, Eri</creatorcontrib><creatorcontrib>Sugimoto, Yoshiyuki</creatorcontrib><creatorcontrib>Kodaira, Hiroshi</creatorcontrib><creatorcontrib>Kato, Yoshimitsu</creatorcontrib><creatorcontrib>Shirakura, Shiro</creatorcontrib><creatorcontrib>Nakasato, Yoshisuke</creatorcontrib><title>Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood–brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.</description><subject>Alkadienes - chemical synthesis</subject><subject>Alkadienes - pharmacokinetics</subject><subject>Alkadienes - pharmacology</subject><subject>Amides - chemical synthesis</subject><subject>Amides - pharmacokinetics</subject><subject>Amides - pharmacology</subject><subject>Analgesics - chemical synthesis</subject><subject>Analgesics - pharmacokinetics</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Calcium - metabolism</subject><subject>Capsaicin - pharmacology</subject><subject>Dogs</subject><subject>Epstein-Barr Virus Nuclear Antigens - genetics</subject><subject>Haplorhini</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Hyperalgesia - prevention & control</subject><subject>Male</subject><subject>Microsomes, Liver - metabolism</subject><subject>Neuralgia - prevention & control</subject><subject>Quinolones - chemical synthesis</subject><subject>Quinolones - pharmacokinetics</subject><subject>Quinolones - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>TRPV Cation Channels - agonists</subject><subject>TRPV Cation Channels - antagonists & inhibitors</subject><subject>TRPV Cation Channels - genetics</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>eNptkE1LAzEQQIMoWqsH_4DkIii4OpNsanMsfoOoSPW6ZJOspGQ3NdkWevC_G6l68jQz8Hgwj5ADhDMEhuezlgMgYLdBBigYFOUYyk0yAGCsYCPGd8huSjMA4Mj4NtlhjMsSoRyQzyuXdFjauKKhoY9581SciuLKqbjyc9v1yjjbqdYZm6hK9Ckq71d0slTOq9pbOo2qSxnp6YvVdt6HSJ9Dn2-nPH1TnfM-OEORHk9fnt_whE6y8z10LvVpj2w1yie7_zOH5PXmenp5Vzw83d5fTh4KxVH0RW2EHDN1Acix1qIZGYnCSCUbOWJsrMXFGBurSwZMcqN1zXBkam1kDZILrvmQHK-98xg-Fjb1VZvftt6rzoZFqjCnKUFAiRk9WaM6hpSibap5dG2OkaHqu3b1Vzuzhz_aRd1a80f-5s3A0RpQOlWzsIhd_vIf0RfrpIXg</recordid><startdate>20120412</startdate><enddate>20120412</enddate><creator>Saku, Osamu</creator><creator>Ishida, Hiroshi</creator><creator>Atsumi, Eri</creator><creator>Sugimoto, Yoshiyuki</creator><creator>Kodaira, Hiroshi</creator><creator>Kato, Yoshimitsu</creator><creator>Shirakura, Shiro</creator><creator>Nakasato, Yoshisuke</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>20120412</creationdate><title>Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists</title><author>Saku, Osamu ; 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Med. Chem</addtitle><date>2012-04-12</date><risdate>2012</risdate><volume>55</volume><issue>7</issue><spage>3436</spage><epage>3451</epage><pages>3436-3451</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood–brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22394104</pmid><doi>10.1021/jm300101n</doi><tpages>16</tpages></addata></record> |
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| source | ACS Publications; MEDLINE |
| subjects | Alkadienes - chemical synthesis Alkadienes - pharmacokinetics Alkadienes - pharmacology Amides - chemical synthesis Amides - pharmacokinetics Amides - pharmacology Analgesics - chemical synthesis Analgesics - pharmacokinetics Analgesics - pharmacology Animals Blood-Brain Barrier - metabolism Calcium - metabolism Capsaicin - pharmacology Dogs Epstein-Barr Virus Nuclear Antigens - genetics Haplorhini HEK293 Cells Humans Hyperalgesia - prevention & control Male Microsomes, Liver - metabolism Neuralgia - prevention & control Quinolones - chemical synthesis Quinolones - pharmacokinetics Quinolones - pharmacology Rats Rats, Sprague-Dawley Stereoisomerism Structure-Activity Relationship TRPV Cation Channels - agonists TRPV Cation Channels - antagonists & inhibitors TRPV Cation Channels - genetics |
| title | Discovery of Novel 5,5-Diarylpentadienamides as Orally Available Transient Receptor Potential Vanilloid 1 (TRPV1) Antagonists |
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