First-in-Class, Dual-Action, 3,5-Disubstituted Indole Derivatives Having Human Nitric Oxide Synthase (nNOS) and Norepinephrine Reuptake Inhibitory (NERI) Activity for the Treatment of Neuropathic Pain
A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure–activity relationship (SAR) within the cyclohexane ri...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-04, Vol.55 (7), p.3488-3501 |
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| container_title | Journal of medicinal chemistry |
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| creator | Mladenova, Gabriela Annedi, Subhash C Ramnauth, Jailall Maddaford, Shawn P Rakhit, Suman Andrews, John S Zhang, Dongqin Porreca, Frank |
| description | A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure–activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain. |
| doi_str_mv | 10.1021/jm300138g |
| format | Article |
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The structure–activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm300138g</identifier><identifier>PMID: 22420844</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Adrenergic Uptake Inhibitors - chemical synthesis ; Adrenergic Uptake Inhibitors - chemistry ; Adrenergic Uptake Inhibitors - pharmacology ; Analgesics - chemical synthesis ; Analgesics - chemistry ; Analgesics - pharmacology ; Animals ; CHO Cells ; Coronary Vessels - drug effects ; Coronary Vessels - physiology ; Cricetinae ; Cricetulus ; Cyclohexanes - chemical synthesis ; Cyclohexanes - chemistry ; Cyclohexanes - pharmacology ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors ; HEK293 Cells ; High-Throughput Screening Assays ; Humans ; In Vitro Techniques ; Indoles - chemical synthesis ; Indoles - chemistry ; Indoles - pharmacology ; Muscle Contraction ; Muscle, Smooth, Vascular - drug effects ; Muscle, Smooth, Vascular - physiology ; Neuralgia - drug therapy ; Nitric Oxide Synthase Type I - antagonists & inhibitors ; Norepinephrine Plasma Membrane Transport Proteins - metabolism ; Rats ; Stereoisomerism ; Structure-Activity Relationship ; Thiophenes - chemical synthesis ; Thiophenes - chemistry ; Thiophenes - pharmacology ; Vascular Resistance</subject><ispartof>Journal of medicinal chemistry, 2012-04, Vol.55 (7), p.3488-3501</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-81c1b1b75efb3827097e89f7a39f34d2ae65cfbf6d8db0454e87092f93e7640d3</citedby><cites>FETCH-LOGICAL-a315t-81c1b1b75efb3827097e89f7a39f34d2ae65cfbf6d8db0454e87092f93e7640d3</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/jm300138g$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm300138g$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22420844$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mladenova, Gabriela</creatorcontrib><creatorcontrib>Annedi, Subhash C</creatorcontrib><creatorcontrib>Ramnauth, Jailall</creatorcontrib><creatorcontrib>Maddaford, Shawn P</creatorcontrib><creatorcontrib>Rakhit, Suman</creatorcontrib><creatorcontrib>Andrews, John S</creatorcontrib><creatorcontrib>Zhang, Dongqin</creatorcontrib><creatorcontrib>Porreca, Frank</creatorcontrib><title>First-in-Class, Dual-Action, 3,5-Disubstituted Indole Derivatives Having Human Nitric Oxide Synthase (nNOS) and Norepinephrine Reuptake Inhibitory (NERI) Activity for the Treatment of Neuropathic Pain</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure–activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.</description><subject>Adrenergic Uptake Inhibitors - chemical synthesis</subject><subject>Adrenergic Uptake Inhibitors - chemistry</subject><subject>Adrenergic Uptake Inhibitors - pharmacology</subject><subject>Analgesics - chemical synthesis</subject><subject>Analgesics - chemistry</subject><subject>Analgesics - pharmacology</subject><subject>Animals</subject><subject>CHO Cells</subject><subject>Coronary Vessels - drug effects</subject><subject>Coronary Vessels - physiology</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cyclohexanes - chemical synthesis</subject><subject>Cyclohexanes - chemistry</subject><subject>Cyclohexanes - pharmacology</subject><subject>ERG1 Potassium Channel</subject><subject>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</subject><subject>HEK293 Cells</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacology</subject><subject>Muscle Contraction</subject><subject>Muscle, Smooth, Vascular - drug effects</subject><subject>Muscle, Smooth, Vascular - physiology</subject><subject>Neuralgia - drug therapy</subject><subject>Nitric Oxide Synthase Type I - antagonists & inhibitors</subject><subject>Norepinephrine Plasma Membrane Transport Proteins - metabolism</subject><subject>Rats</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Thiophenes - chemical synthesis</subject><subject>Thiophenes - chemistry</subject><subject>Thiophenes - pharmacology</subject><subject>Vascular Resistance</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>eNptkctu00AUhkcIRENhwQug2SAlUgxzc-wsq6QlkSoHtWVtje0zzQR7xswlIm_IYzFVSldsztl8-s7lR-gjJV8oYfTrYeCEUF4-vkITmjOSiZKI12hCCGMZWzB-gd55fyCEcMr4W3TBmGCkFGKC_txo50OmTbbqpfdzvI6yz67aoK2ZYz7Ps7X2sfFBhxigw1vT2R7wGpw-yqCP4PFGHrV5xJs4SIMrHZxu8e637gDfn0zYSw94aqrd_QxL0-HKOhi1gXHvUsV3EMcgf0IS73Wjg3UnPK2u77Yz_LTEUYcTVtbhsAf84ECGAUzAVuEKorOjDPs07bvU5j16o2Tv4cNzv0Q_bq4fVpvsdvdtu7q6zSSnechK2tKGNkUOquElK8iygHKpCsmXiouOSVjkrWrUoiu7hohcQJkYppYcioUgHb9E07N3dPZXBB_qQfsW-l4asNHXNH1ZEFHkNKGzM9o6670DVY9OD9KdElQ_BVe_BJfYT8_a2AzQvZD_kkrA5zMgW18fbHQmXfkf0V_qZ6CS</recordid><startdate>20120412</startdate><enddate>20120412</enddate><creator>Mladenova, Gabriela</creator><creator>Annedi, Subhash C</creator><creator>Ramnauth, Jailall</creator><creator>Maddaford, Shawn P</creator><creator>Rakhit, Suman</creator><creator>Andrews, John S</creator><creator>Zhang, Dongqin</creator><creator>Porreca, Frank</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>First-in-Class, Dual-Action, 3,5-Disubstituted Indole Derivatives Having Human Nitric Oxide Synthase (nNOS) and Norepinephrine Reuptake Inhibitory (NERI) Activity for the Treatment of Neuropathic Pain</title><author>Mladenova, Gabriela ; Annedi, Subhash C ; Ramnauth, Jailall ; Maddaford, Shawn P ; Rakhit, Suman ; Andrews, John S ; Zhang, Dongqin ; Porreca, Frank</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-81c1b1b75efb3827097e89f7a39f34d2ae65cfbf6d8db0454e87092f93e7640d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adrenergic Uptake Inhibitors - chemical synthesis</topic><topic>Adrenergic Uptake Inhibitors - chemistry</topic><topic>Adrenergic Uptake Inhibitors - pharmacology</topic><topic>Analgesics - chemical synthesis</topic><topic>Analgesics - chemistry</topic><topic>Analgesics - pharmacology</topic><topic>Animals</topic><topic>CHO Cells</topic><topic>Coronary Vessels - drug effects</topic><topic>Coronary Vessels - physiology</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cyclohexanes - chemical synthesis</topic><topic>Cyclohexanes - chemistry</topic><topic>Cyclohexanes - pharmacology</topic><topic>ERG1 Potassium Channel</topic><topic>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</topic><topic>HEK293 Cells</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacology</topic><topic>Muscle Contraction</topic><topic>Muscle, Smooth, Vascular - drug effects</topic><topic>Muscle, Smooth, Vascular - physiology</topic><topic>Neuralgia - drug therapy</topic><topic>Nitric Oxide Synthase Type I - antagonists & inhibitors</topic><topic>Norepinephrine Plasma Membrane Transport Proteins - metabolism</topic><topic>Rats</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Thiophenes - chemical synthesis</topic><topic>Thiophenes - chemistry</topic><topic>Thiophenes - pharmacology</topic><topic>Vascular Resistance</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mladenova, Gabriela</creatorcontrib><creatorcontrib>Annedi, Subhash C</creatorcontrib><creatorcontrib>Ramnauth, Jailall</creatorcontrib><creatorcontrib>Maddaford, Shawn P</creatorcontrib><creatorcontrib>Rakhit, Suman</creatorcontrib><creatorcontrib>Andrews, John S</creatorcontrib><creatorcontrib>Zhang, Dongqin</creatorcontrib><creatorcontrib>Porreca, Frank</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mladenova, Gabriela</au><au>Annedi, Subhash C</au><au>Ramnauth, Jailall</au><au>Maddaford, Shawn P</au><au>Rakhit, Suman</au><au>Andrews, John S</au><au>Zhang, Dongqin</au><au>Porreca, Frank</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>First-in-Class, Dual-Action, 3,5-Disubstituted Indole Derivatives Having Human Nitric Oxide Synthase (nNOS) and Norepinephrine Reuptake Inhibitory (NERI) Activity for the Treatment of Neuropathic Pain</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2012-04-12</date><risdate>2012</risdate><volume>55</volume><issue>7</issue><spage>3488</spage><epage>3501</epage><pages>3488-3501</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure–activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC50 of 0.56 and 1.0 μM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22420844</pmid><doi>10.1021/jm300138g</doi><tpages>14</tpages></addata></record> |
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| subjects | Adrenergic Uptake Inhibitors - chemical synthesis Adrenergic Uptake Inhibitors - chemistry Adrenergic Uptake Inhibitors - pharmacology Analgesics - chemical synthesis Analgesics - chemistry Analgesics - pharmacology Animals CHO Cells Coronary Vessels - drug effects Coronary Vessels - physiology Cricetinae Cricetulus Cyclohexanes - chemical synthesis Cyclohexanes - chemistry Cyclohexanes - pharmacology ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels - antagonists & inhibitors HEK293 Cells High-Throughput Screening Assays Humans In Vitro Techniques Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Muscle Contraction Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - physiology Neuralgia - drug therapy Nitric Oxide Synthase Type I - antagonists & inhibitors Norepinephrine Plasma Membrane Transport Proteins - metabolism Rats Stereoisomerism Structure-Activity Relationship Thiophenes - chemical synthesis Thiophenes - chemistry Thiophenes - pharmacology Vascular Resistance |
| title | First-in-Class, Dual-Action, 3,5-Disubstituted Indole Derivatives Having Human Nitric Oxide Synthase (nNOS) and Norepinephrine Reuptake Inhibitory (NERI) Activity for the Treatment of Neuropathic Pain |
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