Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors
[Display omitted] Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performe...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2019-08, Vol.27 (16), p.3692-3706 |
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| container_title | Bioorganic & medicinal chemistry |
| container_volume | 27 |
| creator | Chino, Ayaka Honda, Shugo Morita, Masataka Yonezawa, Koichi Hamaguchi, Wataru Amano, Yasushi Moriguchi, Hiroyuki Yamazaki, Mayako Aota, Masaki Tomishima, Masaki Masuda, Naoyuki |
| description | [Display omitted]
Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit. |
| doi_str_mv | 10.1016/j.bmc.2019.07.010 |
| format | Article |
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Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2019.07.010</identifier><identifier>PMID: 31301949</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Brain penetration ; P-gp liability ; PDE10A inhibitor ; Schizophrenia ; Y-maze</subject><ispartof>Bioorganic & medicinal chemistry, 2019-08, Vol.27 (16), p.3692-3706</ispartof><rights>2019 Elsevier Ltd</rights><rights>Copyright © 2019 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-fa8ef702095c9678f830c729668399ebebbe18c33c53c336333b6fe6bce97f2d3</citedby><cites>FETCH-LOGICAL-c353t-fa8ef702095c9678f830c729668399ebebbe18c33c53c336333b6fe6bce97f2d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0968089619309381$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31301949$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chino, Ayaka</creatorcontrib><creatorcontrib>Honda, Shugo</creatorcontrib><creatorcontrib>Morita, Masataka</creatorcontrib><creatorcontrib>Yonezawa, Koichi</creatorcontrib><creatorcontrib>Hamaguchi, Wataru</creatorcontrib><creatorcontrib>Amano, Yasushi</creatorcontrib><creatorcontrib>Moriguchi, Hiroyuki</creatorcontrib><creatorcontrib>Yamazaki, Mayako</creatorcontrib><creatorcontrib>Aota, Masaki</creatorcontrib><creatorcontrib>Tomishima, Masaki</creatorcontrib><creatorcontrib>Masuda, Naoyuki</creatorcontrib><title>Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>[Display omitted]
Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.</description><subject>Brain penetration</subject><subject>P-gp liability</subject><subject>PDE10A inhibitor</subject><subject>Schizophrenia</subject><subject>Y-maze</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kc9q3DAQxkVpaDZpH6CXomMPK0eybNmipyWkSSFQSNpTKUJ_xl0ttrWVbMPmNfLCVdhtjz3MDIjv-xjND6H3jBaMMnG1K8xgi5IyWdCmoIy-QitWiYpwLtlrtKJStIS2Upyji5R2lNKykuwNOueMZ1MlV-j58TBOW0g-rfHj5gGnaXaHNdajw8aHPvzyVvcYFt3PevJhxKHDY1igx-WaE-e3BxcDYXfED97pp_CDrUuifxoYn04vPWAH0S_ZvkDCOuH9NqRczkOaIOoEmNEN9uPWGz-FmN6is073Cd6d5iX6_vnm2_Uduf96--V6c08sr_lEOt1C19CSytpK0bRdy6ltSilEy6UEA8YAay3ntua5C865ER0IY0E2Xen4Jfp4zN3H8HvOy6jBJwt9r0cIc1JlWbesFk1Fs5QdpTaGlCJ0ah_9oONBMapeWKidyizUCwtFG5VZZM-HU_xsBnD_HH-PnwWfjgLIn1w8RJWsh9GC8xHspFzw_4n_A4Imm0A</recordid><startdate>20190815</startdate><enddate>20190815</enddate><creator>Chino, Ayaka</creator><creator>Honda, Shugo</creator><creator>Morita, Masataka</creator><creator>Yonezawa, Koichi</creator><creator>Hamaguchi, Wataru</creator><creator>Amano, Yasushi</creator><creator>Moriguchi, Hiroyuki</creator><creator>Yamazaki, Mayako</creator><creator>Aota, Masaki</creator><creator>Tomishima, Masaki</creator><creator>Masuda, Naoyuki</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20190815</creationdate><title>Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors</title><author>Chino, Ayaka ; Honda, Shugo ; Morita, Masataka ; Yonezawa, Koichi ; Hamaguchi, Wataru ; Amano, Yasushi ; Moriguchi, Hiroyuki ; Yamazaki, Mayako ; Aota, Masaki ; Tomishima, Masaki ; Masuda, Naoyuki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-fa8ef702095c9678f830c729668399ebebbe18c33c53c336333b6fe6bce97f2d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Brain penetration</topic><topic>P-gp liability</topic><topic>PDE10A inhibitor</topic><topic>Schizophrenia</topic><topic>Y-maze</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chino, Ayaka</creatorcontrib><creatorcontrib>Honda, Shugo</creatorcontrib><creatorcontrib>Morita, Masataka</creatorcontrib><creatorcontrib>Yonezawa, Koichi</creatorcontrib><creatorcontrib>Hamaguchi, Wataru</creatorcontrib><creatorcontrib>Amano, Yasushi</creatorcontrib><creatorcontrib>Moriguchi, Hiroyuki</creatorcontrib><creatorcontrib>Yamazaki, Mayako</creatorcontrib><creatorcontrib>Aota, Masaki</creatorcontrib><creatorcontrib>Tomishima, Masaki</creatorcontrib><creatorcontrib>Masuda, Naoyuki</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chino, Ayaka</au><au>Honda, Shugo</au><au>Morita, Masataka</au><au>Yonezawa, Koichi</au><au>Hamaguchi, Wataru</au><au>Amano, Yasushi</au><au>Moriguchi, Hiroyuki</au><au>Yamazaki, Mayako</au><au>Aota, Masaki</au><au>Tomishima, Masaki</au><au>Masuda, Naoyuki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors</atitle><jtitle>Bioorganic & medicinal chemistry</jtitle><addtitle>Bioorg Med Chem</addtitle><date>2019-08-15</date><risdate>2019</risdate><volume>27</volume><issue>16</issue><spage>3692</spage><epage>3706</epage><pages>3692-3706</pages><issn>0968-0896</issn><eissn>1464-3391</eissn><abstract>[Display omitted]
Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31301949</pmid><doi>10.1016/j.bmc.2019.07.010</doi><tpages>15</tpages></addata></record> |
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| subjects | Brain penetration P-gp liability PDE10A inhibitor Schizophrenia Y-maze |
| title | Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors |
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