Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4‑[3-Chloro-5-[(1S)‑1,2-dihydroxyethyl]-2-pyridyl]‑N‑[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro‑2H‑pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management
A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influ...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-08, Vol.57 (15), p.6781-6794 |
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| container_title | Journal of medicinal chemistry |
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| creator | Tafesse, Laykea Kanemasa, Toshiyuki Kurose, Noriyuki Yu, Jianming Asaki, Toshiyuki Wu, Gang Iwamoto, Yuka Yamaguchi, Yoshitaka Ni, Chiyou Engel, John Tsuno, Naoki Patel, Aniket Zhou, Xiaoming Shintani, Takuya Brown, Kevin Hasegawa, Tsuyoshi Shet, Manjunath Iso, Yasuyoshi Kato, Akira Kyle, Donald J |
| description | A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials. |
| doi_str_mv | 10.1021/jm500818a |
| format | Article |
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The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm500818a</identifier><identifier>PMID: 25057800</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Aminopyridines - chemistry ; Aminopyridines - pharmacokinetics ; Aminopyridines - pharmacology ; Analgesics - chemistry ; Analgesics - pharmacokinetics ; Analgesics - pharmacology ; Animals ; Body Temperature - drug effects ; Calcium - metabolism ; Capsaicin - pharmacology ; CHO Cells ; Cricetulus ; Freund's Adjuvant ; Ganglia, Spinal - cytology ; Humans ; Hydrogen-Ion Concentration ; Male ; Pain - drug therapy ; Pain - etiology ; Rats, Sprague-Dawley ; Sensory Receptor Cells - drug effects ; Sensory Receptor Cells - physiology ; Stereoisomerism ; Structure-Activity Relationship ; TRPV Cation Channels - antagonists & inhibitors</subject><ispartof>Journal of medicinal chemistry, 2014-08, Vol.57 (15), p.6781-6794</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm500818a$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm500818a$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25057800$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tafesse, Laykea</creatorcontrib><creatorcontrib>Kanemasa, Toshiyuki</creatorcontrib><creatorcontrib>Kurose, Noriyuki</creatorcontrib><creatorcontrib>Yu, Jianming</creatorcontrib><creatorcontrib>Asaki, Toshiyuki</creatorcontrib><creatorcontrib>Wu, Gang</creatorcontrib><creatorcontrib>Iwamoto, Yuka</creatorcontrib><creatorcontrib>Yamaguchi, Yoshitaka</creatorcontrib><creatorcontrib>Ni, Chiyou</creatorcontrib><creatorcontrib>Engel, John</creatorcontrib><creatorcontrib>Tsuno, Naoki</creatorcontrib><creatorcontrib>Patel, Aniket</creatorcontrib><creatorcontrib>Zhou, Xiaoming</creatorcontrib><creatorcontrib>Shintani, Takuya</creatorcontrib><creatorcontrib>Brown, Kevin</creatorcontrib><creatorcontrib>Hasegawa, Tsuyoshi</creatorcontrib><creatorcontrib>Shet, Manjunath</creatorcontrib><creatorcontrib>Iso, Yasuyoshi</creatorcontrib><creatorcontrib>Kato, Akira</creatorcontrib><creatorcontrib>Kyle, Donald J</creatorcontrib><title>Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4‑[3-Chloro-5-[(1S)‑1,2-dihydroxyethyl]-2-pyridyl]‑N‑[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro‑2H‑pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.</description><subject>Aminopyridines - chemistry</subject><subject>Aminopyridines - pharmacokinetics</subject><subject>Aminopyridines - pharmacology</subject><subject>Analgesics - chemistry</subject><subject>Analgesics - pharmacokinetics</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>Body Temperature - drug effects</subject><subject>Calcium - metabolism</subject><subject>Capsaicin - pharmacology</subject><subject>CHO Cells</subject><subject>Cricetulus</subject><subject>Freund's Adjuvant</subject><subject>Ganglia, Spinal - cytology</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Male</subject><subject>Pain - drug therapy</subject><subject>Pain - etiology</subject><subject>Rats, Sprague-Dawley</subject><subject>Sensory Receptor Cells - drug effects</subject><subject>Sensory Receptor Cells - physiology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>TRPV Cation Channels - antagonists & inhibitors</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNks1u2zAMx71hw5p1O-wFBl0GJEC1SbIVu70F2UcHdFuRZLkUg0HJcsPAlgJZLupbX2HYG_ZJpvRj2IUkyB8J_kEmyRvO3nMm-IdtKxkreAFPkxGXgtGsYNmzZMSYEFRMRXqQvOy6LWMs5SJ9kRwIyWReMDZ6crIMvteh9-b25s9MB7zCMJCFaSCgs90Gd2QZ-gpNR8BW5CN22l0ZPxBXEyDnLhgbyMqD7XAfLYw2u-D8QwWhIWuw2DQOKzJeLc7XfEJmNsCls9gFkt3e_L5I6XzTOO-opBdjvpzEHD8StMLNUHl3PZiwGZpfVNDd4LGKYQS-7xslHQePddPH5vaOmvxH0fRo-jgk0uI0mrsaWkM51eCVu4YWK0PGa86nkucTAlEnmTdoUcfd51EzVhAMqfeaAC35BhYuTRvFvUqe19B05vWDP0x-fv60mp_Ssx9fvs5nZxR4zgMthM5FXSuupuKYa5XxY6EAJC-knGqeZ6I2oHKWm6zIo9G1KSBjqigqqZQy6WHy9n7urletqcqdxxb8UD4eMQLv7gHQXbl1vbdxnZKzcv8c5b_nSP8CuaezYA</recordid><startdate>20140814</startdate><enddate>20140814</enddate><creator>Tafesse, Laykea</creator><creator>Kanemasa, Toshiyuki</creator><creator>Kurose, Noriyuki</creator><creator>Yu, Jianming</creator><creator>Asaki, Toshiyuki</creator><creator>Wu, Gang</creator><creator>Iwamoto, Yuka</creator><creator>Yamaguchi, Yoshitaka</creator><creator>Ni, Chiyou</creator><creator>Engel, John</creator><creator>Tsuno, Naoki</creator><creator>Patel, Aniket</creator><creator>Zhou, Xiaoming</creator><creator>Shintani, Takuya</creator><creator>Brown, Kevin</creator><creator>Hasegawa, Tsuyoshi</creator><creator>Shet, Manjunath</creator><creator>Iso, Yasuyoshi</creator><creator>Kato, Akira</creator><creator>Kyle, Donald J</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20140814</creationdate><title>Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4‑[3-Chloro-5-[(1S)‑1,2-dihydroxyethyl]-2-pyridyl]‑N‑[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro‑2H‑pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management</title><author>Tafesse, Laykea ; Kanemasa, Toshiyuki ; Kurose, Noriyuki ; Yu, Jianming ; Asaki, Toshiyuki ; Wu, Gang ; Iwamoto, Yuka ; Yamaguchi, Yoshitaka ; Ni, Chiyou ; Engel, John ; Tsuno, Naoki ; Patel, Aniket ; Zhou, Xiaoming ; Shintani, Takuya ; Brown, Kevin ; Hasegawa, Tsuyoshi ; Shet, Manjunath ; Iso, Yasuyoshi ; Kato, Akira ; Kyle, Donald J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a171t-82c72ffb1b6291cb4192baa518556c1742feab707e4877e4cfe8a40b88d5bbbe3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Aminopyridines - chemistry</topic><topic>Aminopyridines - pharmacokinetics</topic><topic>Aminopyridines - pharmacology</topic><topic>Analgesics - chemistry</topic><topic>Analgesics - pharmacokinetics</topic><topic>Analgesics - pharmacology</topic><topic>Animals</topic><topic>Body Temperature - drug effects</topic><topic>Calcium - metabolism</topic><topic>Capsaicin - pharmacology</topic><topic>CHO Cells</topic><topic>Cricetulus</topic><topic>Freund's Adjuvant</topic><topic>Ganglia, Spinal - cytology</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Male</topic><topic>Pain - drug therapy</topic><topic>Pain - etiology</topic><topic>Rats, Sprague-Dawley</topic><topic>Sensory Receptor Cells - drug effects</topic><topic>Sensory Receptor Cells - physiology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>TRPV Cation Channels - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tafesse, Laykea</creatorcontrib><creatorcontrib>Kanemasa, Toshiyuki</creatorcontrib><creatorcontrib>Kurose, Noriyuki</creatorcontrib><creatorcontrib>Yu, Jianming</creatorcontrib><creatorcontrib>Asaki, Toshiyuki</creatorcontrib><creatorcontrib>Wu, Gang</creatorcontrib><creatorcontrib>Iwamoto, Yuka</creatorcontrib><creatorcontrib>Yamaguchi, Yoshitaka</creatorcontrib><creatorcontrib>Ni, Chiyou</creatorcontrib><creatorcontrib>Engel, John</creatorcontrib><creatorcontrib>Tsuno, Naoki</creatorcontrib><creatorcontrib>Patel, Aniket</creatorcontrib><creatorcontrib>Zhou, Xiaoming</creatorcontrib><creatorcontrib>Shintani, Takuya</creatorcontrib><creatorcontrib>Brown, Kevin</creatorcontrib><creatorcontrib>Hasegawa, Tsuyoshi</creatorcontrib><creatorcontrib>Shet, Manjunath</creatorcontrib><creatorcontrib>Iso, Yasuyoshi</creatorcontrib><creatorcontrib>Kato, Akira</creatorcontrib><creatorcontrib>Kyle, Donald J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tafesse, Laykea</au><au>Kanemasa, Toshiyuki</au><au>Kurose, Noriyuki</au><au>Yu, Jianming</au><au>Asaki, Toshiyuki</au><au>Wu, Gang</au><au>Iwamoto, Yuka</au><au>Yamaguchi, Yoshitaka</au><au>Ni, Chiyou</au><au>Engel, John</au><au>Tsuno, Naoki</au><au>Patel, Aniket</au><au>Zhou, Xiaoming</au><au>Shintani, Takuya</au><au>Brown, Kevin</au><au>Hasegawa, Tsuyoshi</au><au>Shet, Manjunath</au><au>Iso, Yasuyoshi</au><au>Kato, Akira</au><au>Kyle, Donald J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4‑[3-Chloro-5-[(1S)‑1,2-dihydroxyethyl]-2-pyridyl]‑N‑[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro‑2H‑pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-08-14</date><risdate>2014</risdate><volume>57</volume><issue>15</issue><spage>6781</spage><epage>6794</epage><pages>6781-6794</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25057800</pmid><doi>10.1021/jm500818a</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2014-08, Vol.57 (15), p.6781-6794 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmed_primary_25057800 |
| source | ACS Publications; MEDLINE |
| subjects | Aminopyridines - chemistry Aminopyridines - pharmacokinetics Aminopyridines - pharmacology Analgesics - chemistry Analgesics - pharmacokinetics Analgesics - pharmacology Animals Body Temperature - drug effects Calcium - metabolism Capsaicin - pharmacology CHO Cells Cricetulus Freund's Adjuvant Ganglia, Spinal - cytology Humans Hydrogen-Ion Concentration Male Pain - drug therapy Pain - etiology Rats, Sprague-Dawley Sensory Receptor Cells - drug effects Sensory Receptor Cells - physiology Stereoisomerism Structure-Activity Relationship TRPV Cation Channels - antagonists & inhibitors |
| title | Structure–Activity Relationship Studies and Discovery of a Potent Transient Receptor Potential Vanilloid (TRPV1) Antagonist 4‑[3-Chloro-5-[(1S)‑1,2-dihydroxyethyl]-2-pyridyl]‑N‑[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro‑2H‑pyridine-1-carboxamide (V116517) as a Clinical Candidate for Pain Management |
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