Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1 H-indol-1-yl)-3-phenylpropan-2-ols
A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1 H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enan...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2009-09, Vol.19 (17), p.5029-5032 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Kim, Callain Y. Mahaney, Paige E. McConnell, Oliver Zhang, Yingru Manas, Eric Ho, Douglas M. Deecher, Darlene C. Trybulski, Eugene J. |
| description | A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1
H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (
2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC
50
=
28
nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter. |
| doi_str_mv | 10.1016/j.bmcl.2009.07.053 |
| format | Article |
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H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (
2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC
50
=
28
nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2009.07.053</identifier><identifier>PMID: 19632110</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>5-HT ; Adrenergic Uptake Inhibitors - chemical synthesis ; Adrenergic Uptake Inhibitors - chemistry ; Adrenergic Uptake Inhibitors - pharmacology ; Animals ; Antidepressive Agents - chemical synthesis ; Antidepressive Agents - chemistry ; Antidepressive Agents - pharmacology ; Biological and medical sciences ; Catecholaminergic system ; Cell Line ; CHO Cells ; Cricetinae ; Cricetulus ; Crystallography, X-Ray ; Dogs ; Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors ; Dopamine Plasma Membrane Transport Proteins - metabolism ; Drug Discovery ; Humans ; Medical sciences ; Molecular Conformation ; Monoamine reuptake inhibitor ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Norepiephrine reuptake inhibitor ; Norepinephrine - antagonists & inhibitors ; NRI ; Pharmacology. Drug treatments ; Propanols - chemical synthesis ; Propanols - chemistry ; Propanols - pharmacology ; Recombinant Proteins - antagonists & inhibitors ; Recombinant Proteins - metabolism ; Serotonin Plasma Membrane Transport Proteins - metabolism ; Structure-Activity Relationship ; Vasomotor symptoms</subject><ispartof>Bioorganic & medicinal chemistry letters, 2009-09, Vol.19 (17), p.5029-5032</ispartof><rights>2009 Elsevier Ltd</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c416t-5cca9eb0f2fafe25831e351f8964dd0ecacabfc0a803de469d10f2a19cd1d1e03</citedby><cites>FETCH-LOGICAL-c416t-5cca9eb0f2fafe25831e351f8964dd0ecacabfc0a803de469d10f2a19cd1d1e03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X09010142$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21859754$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19632110$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Callain Y.</creatorcontrib><creatorcontrib>Mahaney, Paige E.</creatorcontrib><creatorcontrib>McConnell, Oliver</creatorcontrib><creatorcontrib>Zhang, Yingru</creatorcontrib><creatorcontrib>Manas, Eric</creatorcontrib><creatorcontrib>Ho, Douglas M.</creatorcontrib><creatorcontrib>Deecher, Darlene C.</creatorcontrib><creatorcontrib>Trybulski, Eugene J.</creatorcontrib><title>Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1 H-indol-1-yl)-3-phenylpropan-2-ols</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1
H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (
2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC
50
=
28
nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.</description><subject>5-HT</subject><subject>Adrenergic Uptake Inhibitors - chemical synthesis</subject><subject>Adrenergic Uptake Inhibitors - chemistry</subject><subject>Adrenergic Uptake Inhibitors - pharmacology</subject><subject>Animals</subject><subject>Antidepressive Agents - chemical synthesis</subject><subject>Antidepressive Agents - chemistry</subject><subject>Antidepressive Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Catecholaminergic system</subject><subject>Cell Line</subject><subject>CHO Cells</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Crystallography, X-Ray</subject><subject>Dogs</subject><subject>Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors</subject><subject>Dopamine Plasma Membrane Transport Proteins - metabolism</subject><subject>Drug Discovery</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Molecular Conformation</subject><subject>Monoamine reuptake inhibitor</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Norepiephrine reuptake inhibitor</subject><subject>Norepinephrine - antagonists & inhibitors</subject><subject>NRI</subject><subject>Pharmacology. Drug treatments</subject><subject>Propanols - chemical synthesis</subject><subject>Propanols - chemistry</subject><subject>Propanols - pharmacology</subject><subject>Recombinant Proteins - antagonists & inhibitors</subject><subject>Recombinant Proteins - metabolism</subject><subject>Serotonin Plasma Membrane Transport Proteins - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Vasomotor symptoms</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90c-P1CAUB3BiNO64-g94ML34K5HKK5SWxItZf6zJJl408UYovGYYW5iFzpr576WZid72RCCf94D3JeQ5sBoYyPe7epjtVDeMqZp1NWv5A7IBIQXlgrUPyYYpyWivxK8L8iTnHWMgmBCPyQUoyRsAtiHxk8823mE6VnGsTBXwT5Uxeczrfo4hmtkHrBIe9ov5jZUPWz_4Jab8rlq2WAFdQaScvoHqmvrg4kSBHqe35Wi_xXCc9inuTaANjVN-Sh6NZsr47Lxekp9fPv-4uqY3379-u_p4Q60AudDWWqNwYGMzmhGbtueAvIWxV1I4x9Aaa4bRMtMz7lBI5aBYA8o6cICMX5LXp77l8tsD5kXP5aM4TSZgPGTdca5kJ7ks8tW9cp1TB4oX2JygTTHnhKPeJz-bdNTA9BqI3uk1EL0GolmnSyCl6MW5-2GY0f0vOSdQwMszMNmaaUwmWJ__uQb6VnWtKO7DyWGZ2p3HpLP1GCw6n9Au2kV_3zv-Ah-EqNc</recordid><startdate>20090901</startdate><enddate>20090901</enddate><creator>Kim, Callain Y.</creator><creator>Mahaney, Paige E.</creator><creator>McConnell, Oliver</creator><creator>Zhang, Yingru</creator><creator>Manas, Eric</creator><creator>Ho, Douglas M.</creator><creator>Deecher, Darlene C.</creator><creator>Trybulski, Eugene J.</creator><general>Elsevier Ltd</general><general>Elsevier</general><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20090901</creationdate><title>Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1 H-indol-1-yl)-3-phenylpropan-2-ols</title><author>Kim, Callain Y. ; Mahaney, Paige E. ; McConnell, Oliver ; Zhang, Yingru ; Manas, Eric ; Ho, Douglas M. ; Deecher, Darlene C. ; Trybulski, Eugene J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c416t-5cca9eb0f2fafe25831e351f8964dd0ecacabfc0a803de469d10f2a19cd1d1e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>5-HT</topic><topic>Adrenergic Uptake Inhibitors - chemical synthesis</topic><topic>Adrenergic Uptake Inhibitors - chemistry</topic><topic>Adrenergic Uptake Inhibitors - pharmacology</topic><topic>Animals</topic><topic>Antidepressive Agents - chemical synthesis</topic><topic>Antidepressive Agents - chemistry</topic><topic>Antidepressive Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Catecholaminergic system</topic><topic>Cell Line</topic><topic>CHO Cells</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Crystallography, X-Ray</topic><topic>Dogs</topic><topic>Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors</topic><topic>Dopamine Plasma Membrane Transport Proteins - metabolism</topic><topic>Drug Discovery</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Molecular Conformation</topic><topic>Monoamine reuptake inhibitor</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Norepiephrine reuptake inhibitor</topic><topic>Norepinephrine - antagonists & inhibitors</topic><topic>NRI</topic><topic>Pharmacology. Drug treatments</topic><topic>Propanols - chemical synthesis</topic><topic>Propanols - chemistry</topic><topic>Propanols - pharmacology</topic><topic>Recombinant Proteins - antagonists & inhibitors</topic><topic>Recombinant Proteins - metabolism</topic><topic>Serotonin Plasma Membrane Transport Proteins - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Vasomotor symptoms</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Callain Y.</creatorcontrib><creatorcontrib>Mahaney, Paige E.</creatorcontrib><creatorcontrib>McConnell, Oliver</creatorcontrib><creatorcontrib>Zhang, Yingru</creatorcontrib><creatorcontrib>Manas, Eric</creatorcontrib><creatorcontrib>Ho, Douglas M.</creatorcontrib><creatorcontrib>Deecher, Darlene C.</creatorcontrib><creatorcontrib>Trybulski, Eugene J.</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Callain Y.</au><au>Mahaney, Paige E.</au><au>McConnell, Oliver</au><au>Zhang, Yingru</au><au>Manas, Eric</au><au>Ho, Douglas M.</au><au>Deecher, Darlene C.</au><au>Trybulski, Eugene J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1 H-indol-1-yl)-3-phenylpropan-2-ols</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2009-09-01</date><risdate>2009</risdate><volume>19</volume><issue>17</issue><spage>5029</spage><epage>5032</epage><pages>5029-5032</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1
H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (
2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC
50
=
28
nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>19632110</pmid><doi>10.1016/j.bmcl.2009.07.053</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2009-09, Vol.19 (17), p.5029-5032 |
| issn | 0960-894X 1464-3405 |
| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | 5-HT Adrenergic Uptake Inhibitors - chemical synthesis Adrenergic Uptake Inhibitors - chemistry Adrenergic Uptake Inhibitors - pharmacology Animals Antidepressive Agents - chemical synthesis Antidepressive Agents - chemistry Antidepressive Agents - pharmacology Biological and medical sciences Catecholaminergic system Cell Line CHO Cells Cricetinae Cricetulus Crystallography, X-Ray Dogs Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors Dopamine Plasma Membrane Transport Proteins - metabolism Drug Discovery Humans Medical sciences Molecular Conformation Monoamine reuptake inhibitor Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Norepiephrine reuptake inhibitor Norepinephrine - antagonists & inhibitors NRI Pharmacology. Drug treatments Propanols - chemical synthesis Propanols - chemistry Propanols - pharmacology Recombinant Proteins - antagonists & inhibitors Recombinant Proteins - metabolism Serotonin Plasma Membrane Transport Proteins - metabolism Structure-Activity Relationship Vasomotor symptoms |
| title | Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1 H-indol-1-yl)-3-phenylpropan-2-ols |
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