Discovery of a Series of 6,7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors
A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and sy...
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| Veröffentlicht in: | Journal of medicinal chemistry 2007-01, Vol.50 (2), p.182-185 |
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| container_end_page | 185 |
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| container_issue | 2 |
| container_start_page | 182 |
| container_title | Journal of medicinal chemistry |
| container_volume | 50 |
| creator | Chappie, Thomas A. Humphrey, John M. Allen, Martin P. Estep, Kimberly G. Fox, Carol B. Lebel, Lorraine A. Liras, Spiros Marr, Eric S. Menniti, Frank S. Pandit, Jayvardhan Schmidt, Christopher J. Tu, Meihua Williams, Robert D. Yang, Feng V. |
| description | A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A. |
| doi_str_mv | 10.1021/jm060653b |
| format | Article |
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Med. Chem</addtitle><description>A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines. From this library emerged an aryl ether pyrrolidyl 6,7-dimethoxyquinazoline series that became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE10A inhibitory potency and selectivity versus PDE3A/B. These efforts culminated in the discovery of 29, a potent and selective brain penetrable inhibitor of PDE10A.</description><subject>Animals</subject><subject>Corpus Striatum - metabolism</subject><subject>Crystallography, X-Ray</subject><subject>Cyclic GMP - metabolism</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Phosphodiesterase Inhibitors - chemical synthesis</subject><subject>Phosphodiesterase Inhibitors - chemistry</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phosphoric Diester Hydrolases - chemistry</subject><subject>Phosphoric Diester Hydrolases - metabolism</subject><subject>Pyrrolidines - chemical synthesis</subject><subject>Pyrrolidines - chemistry</subject><subject>Pyrrolidines - pharmacology</subject><subject>Quinazolines - chemical synthesis</subject><subject>Quinazolines - chemistry</subject><subject>Quinazolines - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkF1P2zAUhq1paJRuF_sDU242CQlvx44dx5dAy5coVIJdW07sCndJXOxkIvz6uWoFN7s555XOc75ehL4S-EmAkl_rFgooeF59QBPCKWBWAvuIJgCUYlrQ_BAdxbgGgJzQ_BM6JILSsuRygpYzF2v_14Yx86tMZw82OBu3ujgReOZa2z_5lxEzvBlD8I0zY_M8uE6_Jt3ZbDmbEzjNrrsnV7neh_gZHax0E-2XfZ6i3xfzx_MrfHt_eX1-eos1I6LHwqxKwyWr6rKiLJ1jObd1LiUXhmrBtTQpAqsJYyC4kLIyFSHWmNQDjORT9GM3dxP882Bjr9r0iW0a3Vk_RFWUknKQW_B4B9bBxxjsSm2Ca3UYFQG1tU-92ZfYb_uhQ9Va807u_UoA3gEu9vblra7DH1WIXHD1uHxQxeJswejdjVok_vuO13VUaz-ELnnyn8X_AI_Wg-Y</recordid><startdate>20070125</startdate><enddate>20070125</enddate><creator>Chappie, Thomas A.</creator><creator>Humphrey, John M.</creator><creator>Allen, Martin P.</creator><creator>Estep, Kimberly G.</creator><creator>Fox, Carol B.</creator><creator>Lebel, Lorraine A.</creator><creator>Liras, Spiros</creator><creator>Marr, Eric S.</creator><creator>Menniti, Frank S.</creator><creator>Pandit, Jayvardhan</creator><creator>Schmidt, Christopher J.</creator><creator>Tu, Meihua</creator><creator>Williams, Robert D.</creator><creator>Yang, Feng V.</creator><general>American Chemical Society</general><scope>BSCLL</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>7X8</scope></search><sort><creationdate>20070125</creationdate><title>Discovery of a Series of 6,7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors</title><author>Chappie, Thomas A. ; 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| source | ACS Publications; MEDLINE |
| subjects | Animals Corpus Striatum - metabolism Crystallography, X-Ray Cyclic GMP - metabolism Mice Models, Molecular Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - chemistry Phosphoric Diester Hydrolases - metabolism Pyrrolidines - chemical synthesis Pyrrolidines - chemistry Pyrrolidines - pharmacology Quinazolines - chemical synthesis Quinazolines - chemistry Quinazolines - pharmacology Structure-Activity Relationship |
| title | Discovery of a Series of 6,7-Dimethoxy-4-pyrrolidylquinazoline PDE10A Inhibitors |
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