Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands
A new series of 1H-benzofuro[3,2-c]pyrazole-3-carboxamides was synthesized. The novel compounds (15–24) were evaluated for their affinity to CB2 and CB1 cannabinoid receptors. The synthesis of the title compounds takes advantage of the acid-catalysed thermal cyclization of bicyclic hydrazone ethyl 2...
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| Veröffentlicht in: | European journal of medicinal chemistry 2014-07, Vol.82, p.281-292 |
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| container_title | European journal of medicinal chemistry |
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| creator | Pinna, Giovanni Loriga, Giovanni Lazzari, Paolo Ruiu, Stefania Falzoi, Matteo Frau, Simona Pau, Amedeo Murineddu, Gabriele Asproni, Battistina Pinna, Gerard A. |
| description | A new series of 1H-benzofuro[3,2-c]pyrazole-3-carboxamides was synthesized. The novel compounds (15–24) were evaluated for their affinity to CB2 and CB1 cannabinoid receptors. The synthesis of the title compounds takes advantage of the acid-catalysed thermal cyclization of bicyclic hydrazone ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)-2-(6-methyl-3-oxo-2,3-dihydrobenzofuran-2-yl)acetate to tricyclic ethyl 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c]pyrazol-3-carboxylate.
All the obtained derivatives showed high affinity to CB2 receptors. Moreover, significant selectivity for CB2 over CB1 receptors was highlighted for lead derivatives amongst the novel series.
The best binding profiles were determined for homologues bearing monocyclic and bicyclic monoterpenic substituents at the carbamoyl group at 3 position of the pyrazole ring (KiCB2 |
| doi_str_mv | 10.1016/j.ejmech.2014.05.055 |
| format | Article |
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All the obtained derivatives showed high affinity to CB2 receptors. Moreover, significant selectivity for CB2 over CB1 receptors was highlighted for lead derivatives amongst the novel series.
The best binding profiles were determined for homologues bearing monocyclic and bicyclic monoterpenic substituents at the carbamoyl group at 3 position of the pyrazole ring (KiCB2 < 4 nM). In particular, the isopinocampheyl-substituted derivative 22 exhibited the highest selectivity for CB2 receptors with Ki values of 3.7 and 2398 nM for CB2 and CB1 receptors, respectively.
Preliminary functional assays evidenced CB2 agonism behaviour for all the assayed novel derivatives.
[Display omitted]
•Synthesis of novel 1H-benzofuro[3,2-c]pyrazole-3-carboxamides 15–24 was reported.•All the novel derivatives showed good affinity to CB2 cannabinoid receptors.•CB2 agonism profile was determined for all the novel compounds by in vitro assays.•Compound 21 evidenced also CB1 agonism profile.</description><identifier>ISSN: 0223-5234</identifier><identifier>EISSN: 1768-3254</identifier><identifier>DOI: 10.1016/j.ejmech.2014.05.055</identifier><identifier>PMID: 24922543</identifier><language>eng</language><publisher>France: Elsevier Masson SAS</publisher><subject>Benzofurans - chemical synthesis ; Benzofurans - chemistry ; Benzofurans - pharmacology ; benzofuro[3,2-c]pyrazole derivatives ; Cannabinoid receptors ; CB2 agonists ; CB2 ligands ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; HL-60 Cells ; Humans ; Ligands ; Molecular Structure ; Monoterpenes ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Receptor, Cannabinoid, CB1 - antagonists & inhibitors ; Receptor, Cannabinoid, CB2 - antagonists & inhibitors ; Structure-Activity Relationship</subject><ispartof>European journal of medicinal chemistry, 2014-07, Vol.82, p.281-292</ispartof><rights>2014 Elsevier Masson SAS</rights><rights>Copyright © 2014 Elsevier Masson SAS. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-cec1a43f2376f054b4a4a0eb18cedc61a1290725e7206cd0f09cc6dfdccb1f973</citedby><cites>FETCH-LOGICAL-c362t-cec1a43f2376f054b4a4a0eb18cedc61a1290725e7206cd0f09cc6dfdccb1f973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejmech.2014.05.055$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24922543$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pinna, Giovanni</creatorcontrib><creatorcontrib>Loriga, Giovanni</creatorcontrib><creatorcontrib>Lazzari, Paolo</creatorcontrib><creatorcontrib>Ruiu, Stefania</creatorcontrib><creatorcontrib>Falzoi, Matteo</creatorcontrib><creatorcontrib>Frau, Simona</creatorcontrib><creatorcontrib>Pau, Amedeo</creatorcontrib><creatorcontrib>Murineddu, Gabriele</creatorcontrib><creatorcontrib>Asproni, Battistina</creatorcontrib><creatorcontrib>Pinna, Gerard A.</creatorcontrib><title>Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands</title><title>European journal of medicinal chemistry</title><addtitle>Eur J Med Chem</addtitle><description>A new series of 1H-benzofuro[3,2-c]pyrazole-3-carboxamides was synthesized. The novel compounds (15–24) were evaluated for their affinity to CB2 and CB1 cannabinoid receptors. The synthesis of the title compounds takes advantage of the acid-catalysed thermal cyclization of bicyclic hydrazone ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)-2-(6-methyl-3-oxo-2,3-dihydrobenzofuran-2-yl)acetate to tricyclic ethyl 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c]pyrazol-3-carboxylate.
All the obtained derivatives showed high affinity to CB2 receptors. Moreover, significant selectivity for CB2 over CB1 receptors was highlighted for lead derivatives amongst the novel series.
The best binding profiles were determined for homologues bearing monocyclic and bicyclic monoterpenic substituents at the carbamoyl group at 3 position of the pyrazole ring (KiCB2 < 4 nM). In particular, the isopinocampheyl-substituted derivative 22 exhibited the highest selectivity for CB2 receptors with Ki values of 3.7 and 2398 nM for CB2 and CB1 receptors, respectively.
Preliminary functional assays evidenced CB2 agonism behaviour for all the assayed novel derivatives.
[Display omitted]
•Synthesis of novel 1H-benzofuro[3,2-c]pyrazole-3-carboxamides 15–24 was reported.•All the novel derivatives showed good affinity to CB2 cannabinoid receptors.•CB2 agonism profile was determined for all the novel compounds by in vitro assays.•Compound 21 evidenced also CB1 agonism profile.</description><subject>Benzofurans - chemical synthesis</subject><subject>Benzofurans - chemistry</subject><subject>Benzofurans - pharmacology</subject><subject>benzofuro[3,2-c]pyrazole derivatives</subject><subject>Cannabinoid receptors</subject><subject>CB2 agonists</subject><subject>CB2 ligands</subject><subject>Cell Line, Tumor</subject><subject>Dose-Response Relationship, Drug</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Ligands</subject><subject>Molecular Structure</subject><subject>Monoterpenes</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Receptor, Cannabinoid, CB1 - antagonists & inhibitors</subject><subject>Receptor, Cannabinoid, CB2 - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0223-5234</issn><issn>1768-3254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LHEEQhhtJ0I3xH4j0MQdnUv05roeALvkQhORgTiJNb0219jK7s3bPLKy_Pr2s5igUFBRPVfE-jJ0KqAUI-3VR02JJ-FRLELoGU8ocsIlo7EWlpNEf2ASkVJWRSh-xTzkvAMBYgEN2JPVUFkRNWLxLEbfYReTrbfIvfUe55n98Grit-TWtXvowpv5encsKH96QS37FN5SyH2JH3Cd8igPhMCbioU98di15pq5M4oZ4Fx_9qs2f2cfgu0wnr_2Y_f3x_W72q7r9_fNmdnVbobJyqJBQeK2CVI0NYPRce-2B5uICqUUrvJBTaKShRoLFFgJMEW0bWsS5CNNGHbMv-7vr1D-PlAe3jBmp6_yK-jE7YbQE0MrsUL1HMfU5JwpuneLSp60T4HaS3cLtJbudZAemlClrZ68fxvmS2v9Lb1YL8G0PUMm5iZRcxkirEiCmIsW1fXz_wz_tAo_o</recordid><startdate>20140723</startdate><enddate>20140723</enddate><creator>Pinna, Giovanni</creator><creator>Loriga, Giovanni</creator><creator>Lazzari, Paolo</creator><creator>Ruiu, Stefania</creator><creator>Falzoi, Matteo</creator><creator>Frau, Simona</creator><creator>Pau, Amedeo</creator><creator>Murineddu, Gabriele</creator><creator>Asproni, Battistina</creator><creator>Pinna, Gerard A.</creator><general>Elsevier Masson SAS</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>20140723</creationdate><title>Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands</title><author>Pinna, Giovanni ; Loriga, Giovanni ; Lazzari, Paolo ; Ruiu, Stefania ; Falzoi, Matteo ; Frau, Simona ; Pau, Amedeo ; Murineddu, Gabriele ; Asproni, Battistina ; Pinna, Gerard A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-cec1a43f2376f054b4a4a0eb18cedc61a1290725e7206cd0f09cc6dfdccb1f973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Benzofurans - chemical synthesis</topic><topic>Benzofurans - chemistry</topic><topic>Benzofurans - pharmacology</topic><topic>benzofuro[3,2-c]pyrazole derivatives</topic><topic>Cannabinoid receptors</topic><topic>CB2 agonists</topic><topic>CB2 ligands</topic><topic>Cell Line, Tumor</topic><topic>Dose-Response Relationship, Drug</topic><topic>HL-60 Cells</topic><topic>Humans</topic><topic>Ligands</topic><topic>Molecular Structure</topic><topic>Monoterpenes</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Receptor, Cannabinoid, CB1 - antagonists & inhibitors</topic><topic>Receptor, Cannabinoid, CB2 - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pinna, Giovanni</creatorcontrib><creatorcontrib>Loriga, Giovanni</creatorcontrib><creatorcontrib>Lazzari, Paolo</creatorcontrib><creatorcontrib>Ruiu, Stefania</creatorcontrib><creatorcontrib>Falzoi, Matteo</creatorcontrib><creatorcontrib>Frau, Simona</creatorcontrib><creatorcontrib>Pau, Amedeo</creatorcontrib><creatorcontrib>Murineddu, Gabriele</creatorcontrib><creatorcontrib>Asproni, Battistina</creatorcontrib><creatorcontrib>Pinna, Gerard 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>MEDLINE - Academic</collection><jtitle>European journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pinna, Giovanni</au><au>Loriga, Giovanni</au><au>Lazzari, Paolo</au><au>Ruiu, Stefania</au><au>Falzoi, Matteo</au><au>Frau, Simona</au><au>Pau, Amedeo</au><au>Murineddu, Gabriele</au><au>Asproni, Battistina</au><au>Pinna, Gerard A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands</atitle><jtitle>European journal of medicinal chemistry</jtitle><addtitle>Eur J Med Chem</addtitle><date>2014-07-23</date><risdate>2014</risdate><volume>82</volume><spage>281</spage><epage>292</epage><pages>281-292</pages><issn>0223-5234</issn><eissn>1768-3254</eissn><abstract>A new series of 1H-benzofuro[3,2-c]pyrazole-3-carboxamides was synthesized. The novel compounds (15–24) were evaluated for their affinity to CB2 and CB1 cannabinoid receptors. The synthesis of the title compounds takes advantage of the acid-catalysed thermal cyclization of bicyclic hydrazone ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)-2-(6-methyl-3-oxo-2,3-dihydrobenzofuran-2-yl)acetate to tricyclic ethyl 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c]pyrazol-3-carboxylate.
All the obtained derivatives showed high affinity to CB2 receptors. Moreover, significant selectivity for CB2 over CB1 receptors was highlighted for lead derivatives amongst the novel series.
The best binding profiles were determined for homologues bearing monocyclic and bicyclic monoterpenic substituents at the carbamoyl group at 3 position of the pyrazole ring (KiCB2 < 4 nM). In particular, the isopinocampheyl-substituted derivative 22 exhibited the highest selectivity for CB2 receptors with Ki values of 3.7 and 2398 nM for CB2 and CB1 receptors, respectively.
Preliminary functional assays evidenced CB2 agonism behaviour for all the assayed novel derivatives.
[Display omitted]
•Synthesis of novel 1H-benzofuro[3,2-c]pyrazole-3-carboxamides 15–24 was reported.•All the novel derivatives showed good affinity to CB2 cannabinoid receptors.•CB2 agonism profile was determined for all the novel compounds by in vitro assays.•Compound 21 evidenced also CB1 agonism profile.</abstract><cop>France</cop><pub>Elsevier Masson SAS</pub><pmid>24922543</pmid><doi>10.1016/j.ejmech.2014.05.055</doi><tpages>12</tpages></addata></record> |
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| identifier | ISSN: 0223-5234 |
| ispartof | European journal of medicinal chemistry, 2014-07, Vol.82, p.281-292 |
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| subjects | Benzofurans - chemical synthesis Benzofurans - chemistry Benzofurans - pharmacology benzofuro[3,2-c]pyrazole derivatives Cannabinoid receptors CB2 agonists CB2 ligands Cell Line, Tumor Dose-Response Relationship, Drug HL-60 Cells Humans Ligands Molecular Structure Monoterpenes Pyrazoles - chemical synthesis Pyrazoles - chemistry Pyrazoles - pharmacology Receptor, Cannabinoid, CB1 - antagonists & inhibitors Receptor, Cannabinoid, CB2 - antagonists & inhibitors Structure-Activity Relationship |
| title | Tricyclic pyrazoles. Part 6. Benzofuro[3,2-c]pyrazole: A versatile architecture for CB2 selective ligands |
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