Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a Novel Clinical AMPA Receptor Positive Modulator
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic...
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| Veröffentlicht in: | Journal of medicinal chemistry 2010-08, Vol.53 (15), p.5801-5812 |
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| container_title | Journal of medicinal chemistry |
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| creator | Ward, Simon E Harries, Mark Aldegheri, Laura Andreotti, Daniele Ballantine, Stuart Bax, Benjamin D Harris, Andrew J Harker, Andy J Lund, Jesper Melarange, Rosemary Mingardi, Anna Mookherjee, Claudette Mosley, Julie Neve, Marta Oliosi, Beatrice Profeta, Roberto Smith, Kathrine J Smith, Paul W Spada, Simone Thewlis, Kevin M Yusaf, Shahnaz P |
| description | A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans. |
| doi_str_mv | 10.1021/jm1005429 |
| format | Article |
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Harries, Mark ; Aldegheri, Laura ; Andreotti, Daniele ; Ballantine, Stuart ; Bax, Benjamin D ; Harris, Andrew J ; Harker, Andy J ; Lund, Jesper ; Melarange, Rosemary ; Mingardi, Anna ; Mookherjee, Claudette ; Mosley, Julie ; Neve, Marta ; Oliosi, Beatrice ; Profeta, Roberto ; Smith, Kathrine J ; Smith, Paul W ; Spada, Simone ; Thewlis, Kevin M ; Yusaf, Shahnaz P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a314t-137f60aea1470a3836f5ae25e1fe7494eb2dfb4a21a88fedb3829faa3aecf1673</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Administration, Oral</topic><topic>Allosteric Regulation</topic><topic>Animals</topic><topic>Biological Availability</topic><topic>Blood Proteins - metabolism</topic><topic>Blood-Brain Barrier - metabolism</topic><topic>Callithrix</topic><topic>Cell Line</topic><topic>Crystallography, X-Ray</topic><topic>Dogs</topic><topic>Humans</topic><topic>Indenes - chemical synthesis</topic><topic>Indenes - pharmacokinetics</topic><topic>Indenes - pharmacology</topic><topic>Macaca fascicularis</topic><topic>Male</topic><topic>Microsomes, Liver - metabolism</topic><topic>Models, Molecular</topic><topic>Protein Binding</topic><topic>Protein Structure, Tertiary</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - pharmacokinetics</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, AMPA - physiology</topic><topic>Species Specificity</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemical synthesis</topic><topic>Sulfonamides - pharmacokinetics</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ward, Simon E</creatorcontrib><creatorcontrib>Harries, Mark</creatorcontrib><creatorcontrib>Aldegheri, Laura</creatorcontrib><creatorcontrib>Andreotti, Daniele</creatorcontrib><creatorcontrib>Ballantine, Stuart</creatorcontrib><creatorcontrib>Bax, Benjamin D</creatorcontrib><creatorcontrib>Harris, Andrew J</creatorcontrib><creatorcontrib>Harker, Andy J</creatorcontrib><creatorcontrib>Lund, Jesper</creatorcontrib><creatorcontrib>Melarange, Rosemary</creatorcontrib><creatorcontrib>Mingardi, Anna</creatorcontrib><creatorcontrib>Mookherjee, Claudette</creatorcontrib><creatorcontrib>Mosley, Julie</creatorcontrib><creatorcontrib>Neve, Marta</creatorcontrib><creatorcontrib>Oliosi, Beatrice</creatorcontrib><creatorcontrib>Profeta, Roberto</creatorcontrib><creatorcontrib>Smith, Kathrine J</creatorcontrib><creatorcontrib>Smith, Paul W</creatorcontrib><creatorcontrib>Spada, Simone</creatorcontrib><creatorcontrib>Thewlis, Kevin M</creatorcontrib><creatorcontrib>Yusaf, Shahnaz P</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>Ward, Simon E</au><au>Harries, Mark</au><au>Aldegheri, Laura</au><au>Andreotti, Daniele</au><au>Ballantine, Stuart</au><au>Bax, Benjamin D</au><au>Harris, Andrew J</au><au>Harker, Andy J</au><au>Lund, Jesper</au><au>Melarange, Rosemary</au><au>Mingardi, Anna</au><au>Mookherjee, Claudette</au><au>Mosley, Julie</au><au>Neve, Marta</au><au>Oliosi, Beatrice</au><au>Profeta, Roberto</au><au>Smith, Kathrine J</au><au>Smith, Paul W</au><au>Spada, Simone</au><au>Thewlis, Kevin M</au><au>Yusaf, Shahnaz P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a Novel Clinical AMPA Receptor Positive Modulator</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2010-08-12</date><risdate>2010</risdate><volume>53</volume><issue>15</issue><spage>5801</spage><epage>5812</epage><pages>5801-5812</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>20614889</pmid><doi>10.1021/jm1005429</doi><tpages>12</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2010-08, Vol.53 (15), p.5801-5812 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society Journals |
| subjects | Administration, Oral Allosteric Regulation Animals Biological Availability Blood Proteins - metabolism Blood-Brain Barrier - metabolism Callithrix Cell Line Crystallography, X-Ray Dogs Humans Indenes - chemical synthesis Indenes - pharmacokinetics Indenes - pharmacology Macaca fascicularis Male Microsomes, Liver - metabolism Models, Molecular Protein Binding Protein Structure, Tertiary Pyridines - chemical synthesis Pyridines - pharmacokinetics Pyridines - pharmacology Rats Rats, Sprague-Dawley Receptors, AMPA - physiology Species Specificity Stereoisomerism Structure-Activity Relationship Sulfonamides - chemical synthesis Sulfonamides - pharmacokinetics Sulfonamides - pharmacology |
| title | Discovery of N-[(2S)-5-(6-Fluoro-3-pyridinyl)-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide, a Novel Clinical AMPA Receptor Positive Modulator |
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