Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke
In investigating potent sodium (Na+) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na+ channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2012/04/01, Vol.60(4), pp.488-498 |
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| creator | Seki, Maki Tsuruta, Osamu Aoyama, Yukio Soejima, Aki Shimada, Hiroshi Nonaka, Hikaru |
| description | In investigating potent sodium (Na+) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na+ channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na+ channels and a significantly low affinity for dopamine D2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na+ channels, which suggests that 4b would act as a use-dependent Na+ channel blocker in sustained depolarization during ischemic stroke. |
| doi_str_mv | 10.1248/cpb.60.488 |
| format | Article |
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The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na+ channels and a significantly low affinity for dopamine D2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. 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Pharm. Bull.</addtitle><description>In investigating potent sodium (Na+) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na+ channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na+ channels and a significantly low affinity for dopamine D2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na+ channels, which suggests that 4b would act as a use-dependent Na+ channel blocker in sustained depolarization during ischemic stroke.</description><subject>2-Propanol - chemistry</subject><subject>2-Propanol - pharmacokinetics</subject><subject>2-Propanol - pharmacology</subject><subject>2-Propanol - therapeutic use</subject><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Infarction, Middle Cerebral Artery - drug therapy</subject><subject>ischemic stroke</subject><subject>Male</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>neuroprotection</subject><subject>Neuroprotective Agents - chemical synthesis</subject><subject>Neuroprotective Agents - pharmacokinetics</subject><subject>Neuroprotective Agents - pharmacology</subject><subject>Neuroprotective Agents - therapeutic use</subject><subject>neurotoxin receptor site 2</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>sodium channel blocker</subject><subject>Sodium Channel Blockers - chemical synthesis</subject><subject>Sodium Channel Blockers - pharmacokinetics</subject><subject>Sodium Channel Blockers - pharmacology</subject><subject>Sodium Channel Blockers - therapeutic use</subject><subject>Stroke - drug therapy</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkstuEzEUhkcIREtgwwMgSyy4SA6-zMVeoRJKQapEpZS15dhnGqceO9gzEXkU3hZHKUFi47M43_n_Y_-uqpeUzCmrxQezXc1bMq-FeFSdU153uGGMP67OCSESM97ys-pZzhtCWEM6_rQ6Y6xu246z8-r3ch_GNWSXkQ4W3ax1GrSJPt45oz263Gk_6dHFgGKPOL4YXIiY4rcNdsHqsPfx1_4dZnib4laH6NFnSG5XJnZQFDO6iSOEES2jddOAFmsdAnj0yUdzDymjPiZU7NFtAj0OB7LYLMcU7-F59aTXPsOLhzqrfny5vF18xdffr74tLq6xaYUYcSM1a2QnqbE910LYDjjwTlu7AiCiMbYGZmQtaNcAAeD1SkpriWU9a3rR81n15qhbrvBzgjyqwWUD3usAccpKtlyww1HI1_-RmzilUJZTtG5J3QhWHnVWvT9SJsWcE_Rqm9yg015Rog55qZKXaokqeRX41YPktBrAntC_ARXg6giU7iGRGLwL8M_Y5M6sYXCKEcoUIS0hdSlSkSKvSNO1tO1oJ2VR-nhU2uRR38HJSqfRGQ-nrY7HYfrUKZ9CQeB_AEyHv2A</recordid><startdate>2012</startdate><enddate>2012</enddate><creator>Seki, Maki</creator><creator>Tsuruta, Osamu</creator><creator>Aoyama, Yukio</creator><creator>Soejima, Aki</creator><creator>Shimada, Hiroshi</creator><creator>Nonaka, Hikaru</creator><general>The Pharmaceutical Society of Japan</general><general>Pharmaceutical Society of Japan</general><general>Japan Science and Technology Agency</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>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>2012</creationdate><title>Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke</title><author>Seki, Maki ; Tsuruta, Osamu ; Aoyama, Yukio ; Soejima, Aki ; Shimada, Hiroshi ; Nonaka, Hikaru</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c688t-59a259791cdf3a88d7e3e37addbee085cd4e2c948175e0ee34b99dd0d2f25f8f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>2-Propanol - chemistry</topic><topic>2-Propanol - pharmacokinetics</topic><topic>2-Propanol - pharmacology</topic><topic>2-Propanol - therapeutic use</topic><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Infarction, Middle Cerebral Artery - drug therapy</topic><topic>ischemic stroke</topic><topic>Male</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>neuroprotection</topic><topic>Neuroprotective Agents - chemical synthesis</topic><topic>Neuroprotective Agents - pharmacokinetics</topic><topic>Neuroprotective Agents - pharmacology</topic><topic>Neuroprotective Agents - therapeutic use</topic><topic>neurotoxin receptor site 2</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>sodium channel blocker</topic><topic>Sodium Channel Blockers - chemical synthesis</topic><topic>Sodium Channel Blockers - pharmacokinetics</topic><topic>Sodium Channel Blockers - pharmacology</topic><topic>Sodium Channel Blockers - therapeutic use</topic><topic>Stroke - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Seki, Maki</creatorcontrib><creatorcontrib>Tsuruta, Osamu</creatorcontrib><creatorcontrib>Aoyama, Yukio</creatorcontrib><creatorcontrib>Soejima, Aki</creatorcontrib><creatorcontrib>Shimada, Hiroshi</creatorcontrib><creatorcontrib>Nonaka, Hikaru</creatorcontrib><creatorcontrib>Pharmacology Research Laboratories I</creatorcontrib><creatorcontrib>Pharmacology Research Laboratories II</creatorcontrib><creatorcontrib>Medicinal Chemistry Research Laboratories I</creatorcontrib><creatorcontrib>Discovery Screening Center</creatorcontrib><creatorcontrib>Mitsubishi Tanabe Pharma Corporation</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemical & pharmaceutical bulletin</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Seki, Maki</au><au>Tsuruta, Osamu</au><au>Aoyama, Yukio</au><au>Soejima, Aki</au><au>Shimada, Hiroshi</au><au>Nonaka, Hikaru</au><aucorp>Pharmacology Research Laboratories I</aucorp><aucorp>Pharmacology Research Laboratories II</aucorp><aucorp>Medicinal Chemistry Research Laboratories I</aucorp><aucorp>Discovery Screening Center</aucorp><aucorp>Mitsubishi Tanabe Pharma Corporation</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2012</date><risdate>2012</risdate><volume>60</volume><issue>4</issue><spage>488</spage><epage>498</epage><pages>488-498</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>In investigating potent sodium (Na+) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na+ channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na+ channels and a significantly low affinity for dopamine D2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. 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| subjects | 2-Propanol - chemistry 2-Propanol - pharmacokinetics 2-Propanol - pharmacology 2-Propanol - therapeutic use Animals Disease Models, Animal Infarction, Middle Cerebral Artery - drug therapy ischemic stroke Male Microsomes, Liver - drug effects Microsomes, Liver - metabolism neuroprotection Neuroprotective Agents - chemical synthesis Neuroprotective Agents - pharmacokinetics Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use neurotoxin receptor site 2 Rats Rats, Wistar sodium channel blocker Sodium Channel Blockers - chemical synthesis Sodium Channel Blockers - pharmacokinetics Sodium Channel Blockers - pharmacology Sodium Channel Blockers - therapeutic use Stroke - drug therapy |
| title | Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke |
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