Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain
We reported that 2-(3,4-difluorophenylethynyl)- N 6 -3-chlorobenzyl ( N )-methanocarba adenosine derivative 1 (MRS5698) binds selectively to human and mouse A 3 adenosine receptors (A 3 ARs, K i 3 nM). It is becoming an important pharmacological tool for defining A 3 AR effects and is orally active...
Gespeichert in:
| Veröffentlicht in: | Purinergic signalling 2015-09, Vol.11 (3), p.371-387 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 387 |
|---|---|
| container_issue | 3 |
| container_start_page | 371 |
| container_title | Purinergic signalling |
| container_volume | 11 |
| creator | Tosh, Dilip K. Padia, Janak Salvemini, Daniela Jacobson, Kenneth A. |
| description | We reported that 2-(3,4-difluorophenylethynyl)-
N
6
-3-chlorobenzyl (
N
)-methanocarba adenosine derivative
1
(MRS5698) binds selectively to human and mouse A
3
adenosine receptors (A
3
ARs,
K
i
3 nM). It is becoming an important pharmacological tool for defining A
3
AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from
d
-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at |
| doi_str_mv | 10.1007/s11302-015-9459-2 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4529848</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>26111639</sourcerecordid><originalsourceid>FETCH-LOGICAL-c442t-c6bd60acbccf7036878bb02fcd19c72ce22cf21f29257243d23847f275a300203</originalsourceid><addsrcrecordid>eNp9kdtqFTEUhoMotlYfwBvJA3RqspI55EYopVqhIni4DpnMykzKNBmS7MJ-Hx-0KVs3euNVFvkPC9ZHyFvOLjhj_fvMuWDQMN42SraqgWfklLe9aFQru-fHWQwn5FXOd4y1EoR6SU6g45x3Qp2SX9fOeesxlHO6mjRjk61ZkeZ9KAtmn6kJE90S2tUHXyWay27ymGl09Mu3722nhnNq6OLnZd3TjCva4h-QXgpqJgwx-4C0xnErMVEzx-BzoWUxpbbGUt11xWx8qL92SVW2NOAuxc2Upc5blV6TF86sGd_8fs_Iz4_XP65umtuvnz5fXd42Vkooje3GqWPGjta6nolu6IdxZODsxJXtwSKAdcAdKGh7kGICMcjeQd8awRgwcUY-HHq33XiPk61XSWbVW_L3Ju11NF7_qwS_6Dk-aNmCGuRQC_ihwKaYc0J3zHKmn5DpAzJdkeknZBpq5t3fS4-JP4yqAQ6GXKUwY9J3cZdCPcR_Wh8B0Lil6g</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain</title><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>SpringerLink Journals - AutoHoldings</source><creator>Tosh, Dilip K. ; Padia, Janak ; Salvemini, Daniela ; Jacobson, Kenneth A.</creator><creatorcontrib>Tosh, Dilip K. ; Padia, Janak ; Salvemini, Daniela ; Jacobson, Kenneth A.</creatorcontrib><description>We reported that 2-(3,4-difluorophenylethynyl)-
N
6
-3-chlorobenzyl (
N
)-methanocarba adenosine derivative
1
(MRS5698) binds selectively to human and mouse A
3
adenosine receptors (A
3
ARs,
K
i
3 nM). It is becoming an important pharmacological tool for defining A
3
AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from
d
-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed
t
1/2
of 1.09 h and plasma C
max
of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.</description><identifier>ISSN: 1573-9538</identifier><identifier>EISSN: 1573-9546</identifier><identifier>DOI: 10.1007/s11302-015-9459-2</identifier><identifier>PMID: 26111639</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Adenosine - analogs & derivatives ; Adenosine - pharmacokinetics ; Adenosine - therapeutic use ; Adenosine - toxicity ; Adenosine A3 Receptor Agonists - pharmacokinetics ; Adenosine A3 Receptor Agonists - therapeutic use ; Adenosine A3 Receptor Agonists - toxicity ; Animals ; Biological Transport, Active ; Biomedical and Life Sciences ; Biomedicine ; Blood Proteins - metabolism ; Caco-2 Cells ; Cancer Research ; Chronic Disease ; Constriction, Pathologic - complications ; Half-Life ; Human Physiology ; Humans ; In Vitro Techniques ; Male ; Microsomes, Liver ; Mutagenicity Tests ; Neuralgia - drug therapy ; Neurosciences ; Original ; Original Article ; Pharmacology/Toxicology ; Protein Binding ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Purinergic signalling, 2015-09, Vol.11 (3), p.371-387</ispartof><rights>Springer Science+Business Media Dordrecht (outside the USA) 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-c6bd60acbccf7036878bb02fcd19c72ce22cf21f29257243d23847f275a300203</citedby><cites>FETCH-LOGICAL-c442t-c6bd60acbccf7036878bb02fcd19c72ce22cf21f29257243d23847f275a300203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529848/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529848/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26111639$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tosh, Dilip K.</creatorcontrib><creatorcontrib>Padia, Janak</creatorcontrib><creatorcontrib>Salvemini, Daniela</creatorcontrib><creatorcontrib>Jacobson, Kenneth A.</creatorcontrib><title>Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain</title><title>Purinergic signalling</title><addtitle>Purinergic Signalling</addtitle><addtitle>Purinergic Signal</addtitle><description>We reported that 2-(3,4-difluorophenylethynyl)-
N
6
-3-chlorobenzyl (
N
)-methanocarba adenosine derivative
1
(MRS5698) binds selectively to human and mouse A
3
adenosine receptors (A
3
ARs,
K
i
3 nM). It is becoming an important pharmacological tool for defining A
3
AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from
d
-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed
t
1/2
of 1.09 h and plasma C
max
of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.</description><subject>Adenosine - analogs & derivatives</subject><subject>Adenosine - pharmacokinetics</subject><subject>Adenosine - therapeutic use</subject><subject>Adenosine - toxicity</subject><subject>Adenosine A3 Receptor Agonists - pharmacokinetics</subject><subject>Adenosine A3 Receptor Agonists - therapeutic use</subject><subject>Adenosine A3 Receptor Agonists - toxicity</subject><subject>Animals</subject><subject>Biological Transport, Active</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Blood Proteins - metabolism</subject><subject>Caco-2 Cells</subject><subject>Cancer Research</subject><subject>Chronic Disease</subject><subject>Constriction, Pathologic - complications</subject><subject>Half-Life</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Microsomes, Liver</subject><subject>Mutagenicity Tests</subject><subject>Neuralgia - drug therapy</subject><subject>Neurosciences</subject><subject>Original</subject><subject>Original Article</subject><subject>Pharmacology/Toxicology</subject><subject>Protein Binding</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>1573-9538</issn><issn>1573-9546</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kdtqFTEUhoMotlYfwBvJA3RqspI55EYopVqhIni4DpnMykzKNBmS7MJ-Hx-0KVs3euNVFvkPC9ZHyFvOLjhj_fvMuWDQMN42SraqgWfklLe9aFQru-fHWQwn5FXOd4y1EoR6SU6g45x3Qp2SX9fOeesxlHO6mjRjk61ZkeZ9KAtmn6kJE90S2tUHXyWay27ymGl09Mu3722nhnNq6OLnZd3TjCva4h-QXgpqJgwx-4C0xnErMVEzx-BzoWUxpbbGUt11xWx8qL92SVW2NOAuxc2Upc5blV6TF86sGd_8fs_Iz4_XP65umtuvnz5fXd42Vkooje3GqWPGjta6nolu6IdxZODsxJXtwSKAdcAdKGh7kGICMcjeQd8awRgwcUY-HHq33XiPk61XSWbVW_L3Ju11NF7_qwS_6Dk-aNmCGuRQC_ihwKaYc0J3zHKmn5DpAzJdkeknZBpq5t3fS4-JP4yqAQ6GXKUwY9J3cZdCPcR_Wh8B0Lil6g</recordid><startdate>20150901</startdate><enddate>20150901</enddate><creator>Tosh, Dilip K.</creator><creator>Padia, Janak</creator><creator>Salvemini, Daniela</creator><creator>Jacobson, Kenneth A.</creator><general>Springer Netherlands</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>20150901</creationdate><title>Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain</title><author>Tosh, Dilip K. ; Padia, Janak ; Salvemini, Daniela ; Jacobson, Kenneth A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-c6bd60acbccf7036878bb02fcd19c72ce22cf21f29257243d23847f275a300203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenosine - analogs & derivatives</topic><topic>Adenosine - pharmacokinetics</topic><topic>Adenosine - therapeutic use</topic><topic>Adenosine - toxicity</topic><topic>Adenosine A3 Receptor Agonists - pharmacokinetics</topic><topic>Adenosine A3 Receptor Agonists - therapeutic use</topic><topic>Adenosine A3 Receptor Agonists - toxicity</topic><topic>Animals</topic><topic>Biological Transport, Active</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Blood Proteins - metabolism</topic><topic>Caco-2 Cells</topic><topic>Cancer Research</topic><topic>Chronic Disease</topic><topic>Constriction, Pathologic - complications</topic><topic>Half-Life</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Microsomes, Liver</topic><topic>Mutagenicity Tests</topic><topic>Neuralgia - drug therapy</topic><topic>Neurosciences</topic><topic>Original</topic><topic>Original Article</topic><topic>Pharmacology/Toxicology</topic><topic>Protein Binding</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tosh, Dilip K.</creatorcontrib><creatorcontrib>Padia, Janak</creatorcontrib><creatorcontrib>Salvemini, Daniela</creatorcontrib><creatorcontrib>Jacobson, Kenneth A.</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>Purinergic signalling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tosh, Dilip K.</au><au>Padia, Janak</au><au>Salvemini, Daniela</au><au>Jacobson, Kenneth A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain</atitle><jtitle>Purinergic signalling</jtitle><stitle>Purinergic Signalling</stitle><addtitle>Purinergic Signal</addtitle><date>2015-09-01</date><risdate>2015</risdate><volume>11</volume><issue>3</issue><spage>371</spage><epage>387</epage><pages>371-387</pages><issn>1573-9538</issn><eissn>1573-9546</eissn><abstract>We reported that 2-(3,4-difluorophenylethynyl)-
N
6
-3-chlorobenzyl (
N
)-methanocarba adenosine derivative
1
(MRS5698) binds selectively to human and mouse A
3
adenosine receptors (A
3
ARs,
K
i
3 nM). It is becoming an important pharmacological tool for defining A
3
AR effects and is orally active in a chronic neuropathic pain model. Here, we introduce a new synthetic route for MRS5698 from
d
-ribose, suitable for a scale-up on a multi-gram scale, and we measure in vitro and in vivo ADME-Tox parameters. MRS5698 was very stable in vitro, failed to inhibit CYPs at <10 μM, and was largely bound to plasma proteins. It was well tolerated in the rat at doses of ≤200 mg/kg i.p. A 1 mg/kg i.p. dose in the mouse displayed
t
1/2
of 1.09 h and plasma C
max
of 204 nM at 1 h with an AUC of 213 ng × h/mL. CACO-2 bidirectional transport studies suggested intestinal efflux of MRS5698 (efflux ratio 86). Although the oral %F is only 5 %, the beneficial effect to reverse pain lasted for at least 2 h in the CCI model in rats, using the same vehicle for oral administration of a high dose. The stability, low toxicity, lack of CYP interaction, pharmacokinetic half-life, and in vivo efficacy suggest that MRS5698 is a preferred compound for further consideration as a treatment for neuropathic pain.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>26111639</pmid><doi>10.1007/s11302-015-9459-2</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1573-9538 |
| ispartof | Purinergic signalling, 2015-09, Vol.11 (3), p.371-387 |
| issn | 1573-9538 1573-9546 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4529848 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | Adenosine - analogs & derivatives Adenosine - pharmacokinetics Adenosine - therapeutic use Adenosine - toxicity Adenosine A3 Receptor Agonists - pharmacokinetics Adenosine A3 Receptor Agonists - therapeutic use Adenosine A3 Receptor Agonists - toxicity Animals Biological Transport, Active Biomedical and Life Sciences Biomedicine Blood Proteins - metabolism Caco-2 Cells Cancer Research Chronic Disease Constriction, Pathologic - complications Half-Life Human Physiology Humans In Vitro Techniques Male Microsomes, Liver Mutagenicity Tests Neuralgia - drug therapy Neurosciences Original Original Article Pharmacology/Toxicology Protein Binding Rats Rats, Sprague-Dawley |
| title | Efficient, large-scale synthesis and preclinical studies of MRS5698, a highly selective A3 adenosine receptor agonist that protects against chronic neuropathic pain |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T05%3A26%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Efficient,%20large-scale%20synthesis%20and%20preclinical%20studies%20of%20MRS5698,%20a%20highly%20selective%20A3%20adenosine%20receptor%20agonist%20that%20protects%20against%20chronic%20neuropathic%20pain&rft.jtitle=Purinergic%20signalling&rft.au=Tosh,%20Dilip%20K.&rft.date=2015-09-01&rft.volume=11&rft.issue=3&rft.spage=371&rft.epage=387&rft.pages=371-387&rft.issn=1573-9538&rft.eissn=1573-9546&rft_id=info:doi/10.1007/s11302-015-9459-2&rft_dat=%3Cpubmed_cross%3E26111639%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/26111639&rfr_iscdi=true |