Tetrahydro-naphthols as orally available TRPV1 inhibitors
Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead’s phenol structure whilst maintaining potency. Compound rac-6a is an orally av...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (10), p.3408-3411 |
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| container_end_page | 3411 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 22 |
| creator | Urbahns, Klaus Yura, Takeshi Gupta, Jang B. Tajimi, Masaomi Fujishima, Hiroshi Masuda, Tsutomu Yamamoto, Noriyuki Ikegami, Yuka Marumo, Makiko Yasoshima, Kayo Yoshida, Nagahiro Moriwaki, Toshiya Madge, David Chan, Fiona Mogi, Muneto |
| description | Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead’s phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level. |
| doi_str_mv | 10.1016/j.bmcl.2012.03.108 |
| format | Article |
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All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-d57a33792cf7766531e2fae837e305b33adede5e6e016e678985a453fdb629de3</citedby><cites>FETCH-LOGICAL-c435t-d57a33792cf7766531e2fae837e305b33adede5e6e016e678985a453fdb629de3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2012.03.108$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25888583$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22525313$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Urbahns, Klaus</creatorcontrib><creatorcontrib>Yura, Takeshi</creatorcontrib><creatorcontrib>Gupta, Jang B.</creatorcontrib><creatorcontrib>Tajimi, Masaomi</creatorcontrib><creatorcontrib>Fujishima, Hiroshi</creatorcontrib><creatorcontrib>Masuda, Tsutomu</creatorcontrib><creatorcontrib>Yamamoto, Noriyuki</creatorcontrib><creatorcontrib>Ikegami, Yuka</creatorcontrib><creatorcontrib>Marumo, Makiko</creatorcontrib><creatorcontrib>Yasoshima, Kayo</creatorcontrib><creatorcontrib>Yoshida, Nagahiro</creatorcontrib><creatorcontrib>Moriwaki, Toshiya</creatorcontrib><creatorcontrib>Madge, David</creatorcontrib><creatorcontrib>Chan, Fiona</creatorcontrib><creatorcontrib>Mogi, Muneto</creatorcontrib><title>Tetrahydro-naphthols as orally available TRPV1 inhibitors</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Starting from a naphthol-based lead series with low oral bioavailability, we have identified potent TRPV1 antagonists with oral bioavailability in rats. These compounds emerged from SAR studies aimed at replacing the lead’s phenol structure whilst maintaining potency. Compound rac-6a is an orally available TRPV1 antagonist with single-digit nanomolar activity. The enantiomers show a low eudismic ratio at the receptor level.</description><subject>Administration, Oral</subject><subject>Animals</subject><subject>antagonists</subject><subject>bioavailability</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>enantiomers</subject><subject>Medical sciences</subject><subject>Naphthols</subject><subject>Naphthols - administration & dosage</subject><subject>Naphthols - pharmacokinetics</subject><subject>Naphthols - pharmacology</subject><subject>Oral bioavailability</subject><subject>Pharmacology. Drug treatments</subject><subject>phenol</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>TRPV Cation Channels - antagonists & inhibitors</subject><subject>TRPV1</subject><subject>Urinary incontinence</subject><subject>Vanilloid receptor antagonist</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90E2LFDEQBuAgiju7-gc8aF-EvfSY706DF1n8ggVFZ8VbqE6qnQyZzmzSszD_3gwz6s1ToHiqKvUS8oLRJaNMv9ksh62LS04ZX1JRa-YRWTCpZSskVY_JgvaatqaXPy_IZSkbSpmkUj4lF5wrrgQTC9KvcM6wPvic2gl263mdYmmgNClDjIcGHiBEGCI2q29ff7AmTOswhDnl8ow8GSEWfH5-r8jdh_erm0_t7ZePn2_e3bZOCjW3XnUgRNdzN3ad1nUr8hHQiA4FVYMQ4NGjQo31JNSd6Y0CqcToB817j-KKXJ_m7nK632OZ7TYUhzHChGlfbI2CKcl4pyvlJ-pyKiXjaHc5bCEfKjo6bTf2GJk9RmapqDVTm16e5--HLfq_LX8yquD1GUBxEMcMkwvln1PGGGWO7tXJjZAs_MrV3H2vm1TNXVDdsSrengTWvB4CZltcwMmhDxndbH0K__vpb8FSkdQ</recordid><startdate>20120515</startdate><enddate>20120515</enddate><creator>Urbahns, Klaus</creator><creator>Yura, Takeshi</creator><creator>Gupta, Jang B.</creator><creator>Tajimi, Masaomi</creator><creator>Fujishima, Hiroshi</creator><creator>Masuda, Tsutomu</creator><creator>Yamamoto, Noriyuki</creator><creator>Ikegami, Yuka</creator><creator>Marumo, Makiko</creator><creator>Yasoshima, Kayo</creator><creator>Yoshida, Nagahiro</creator><creator>Moriwaki, Toshiya</creator><creator>Madge, David</creator><creator>Chan, Fiona</creator><creator>Mogi, Muneto</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><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>20120515</creationdate><title>Tetrahydro-naphthols as orally available TRPV1 inhibitors</title><author>Urbahns, Klaus ; Yura, Takeshi ; Gupta, Jang B. ; Tajimi, Masaomi ; Fujishima, Hiroshi ; Masuda, Tsutomu ; Yamamoto, Noriyuki ; Ikegami, Yuka ; Marumo, Makiko ; Yasoshima, Kayo ; Yoshida, Nagahiro ; Moriwaki, Toshiya ; Madge, David ; Chan, Fiona ; Mogi, Muneto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-d57a33792cf7766531e2fae837e305b33adede5e6e016e678985a453fdb629de3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Administration, Oral</topic><topic>Animals</topic><topic>antagonists</topic><topic>bioavailability</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>enantiomers</topic><topic>Medical sciences</topic><topic>Naphthols</topic><topic>Naphthols - administration & dosage</topic><topic>Naphthols - pharmacokinetics</topic><topic>Naphthols - pharmacology</topic><topic>Oral bioavailability</topic><topic>Pharmacology. 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| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2012-05, Vol.22 (10), p.3408-3411 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Administration, Oral Animals antagonists bioavailability Biological and medical sciences Biological Availability enantiomers Medical sciences Naphthols Naphthols - administration & dosage Naphthols - pharmacokinetics Naphthols - pharmacology Oral bioavailability Pharmacology. Drug treatments phenol Rats Rats, Sprague-Dawley TRPV Cation Channels - antagonists & inhibitors TRPV1 Urinary incontinence Vanilloid receptor antagonist |
| title | Tetrahydro-naphthols as orally available TRPV1 inhibitors |
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