Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptom...
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| Veröffentlicht in: | Chemical & pharmaceutical bulletin 2018/03/01, Vol.66(3), pp.243-250 |
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| creator | Kadoh, Yoichi Miyoshi, Haruko Matsumura, Takehiko Tanaka, Yoshihito Hongu, Mitsuya Kimura, Mayumi Takedomi, Kei Omori, Kenji Kotera, Jun Sasaki, Takashi Kobayashi, Tamaki Taniguchi, Hiroyuki Watanabe, Yumi Kojima, Koki Sakamoto, Toshiaki Himiyama, Toshiyuki Kawanishi, Eiji |
| description | Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics. |
| doi_str_mv | 10.1248/cpb.c17-00783 |
| format | Article |
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Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.</description><identifier>ISSN: 0009-2363</identifier><identifier>EISSN: 1347-5223</identifier><identifier>DOI: 10.1248/cpb.c17-00783</identifier><identifier>PMID: 29491258</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Animals ; Avoidance behavior ; Avoidance Learning - drug effects ; Binding Sites ; Brain ; conditioned avoidance response (CAR) ; Conditioning ; Crystallography, X-Ray ; Cyclic AMP ; Cyclic GMP ; Drug Evaluation, Preclinical ; Erectile dysfunction ; Homology ; Hydrolase ; Inhibitors ; Inhibitory Concentration 50 ; Mental disorders ; Molecular Dynamics Simulation ; Neostriatum ; Neurons ; Optimization ; Penetration ; Pharmacokinetics ; Pharmacology ; Phosphodiesterase ; phosphodiesterase (PDE) 10A ; Phosphodiesterase Inhibitors - chemistry ; Phosphodiesterase Inhibitors - metabolism ; Phosphodiesterase Inhibitors - pharmacology ; Phosphoric Diester Hydrolases - chemistry ; Phosphoric Diester Hydrolases - metabolism ; Psychosis ; pyrimidine ; Pyrimidines - chemical synthesis ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Quinoxaline ; Quinoxalines ; Quinoxalines - chemical synthesis ; Quinoxalines - chemistry ; Quinoxalines - pharmacology ; Rats ; Rodents ; Schizophrenia ; Signs and symptoms ; Spiny neurons ; Stilbene ; Structure-Activity Relationship ; Tetrahydro-2H-pyran</subject><ispartof>Chemical and Pharmaceutical Bulletin, 2018/03/01, Vol.66(3), pp.243-250</ispartof><rights>2018 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c702t-e15422994d4faa9dc536211930440ce0fc548a6d9890796451103e80f7b30c123</citedby><cites>FETCH-LOGICAL-c702t-e15422994d4faa9dc536211930440ce0fc548a6d9890796451103e80f7b30c123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,1877,4010,27904,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29491258$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kadoh, Yoichi</creatorcontrib><creatorcontrib>Miyoshi, Haruko</creatorcontrib><creatorcontrib>Matsumura, Takehiko</creatorcontrib><creatorcontrib>Tanaka, Yoshihito</creatorcontrib><creatorcontrib>Hongu, Mitsuya</creatorcontrib><creatorcontrib>Kimura, Mayumi</creatorcontrib><creatorcontrib>Takedomi, Kei</creatorcontrib><creatorcontrib>Omori, Kenji</creatorcontrib><creatorcontrib>Kotera, Jun</creatorcontrib><creatorcontrib>Sasaki, Takashi</creatorcontrib><creatorcontrib>Kobayashi, Tamaki</creatorcontrib><creatorcontrib>Taniguchi, Hiroyuki</creatorcontrib><creatorcontrib>Watanabe, Yumi</creatorcontrib><creatorcontrib>Kojima, Koki</creatorcontrib><creatorcontrib>Sakamoto, Toshiaki</creatorcontrib><creatorcontrib>Himiyama, Toshiyuki</creatorcontrib><creatorcontrib>Kawanishi, Eiji</creatorcontrib><creatorcontrib>Nagoya University</creatorcontrib><creatorcontrib>Laboratory of Target and Drug Discovery</creatorcontrib><creatorcontrib>bMitsubishi Tanabe Pharma Corporation</creatorcontrib><creatorcontrib>aMitsubishi Tanabe Pharma Corporation</creatorcontrib><creatorcontrib>Graduate School of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>cIndustry and Academia Cooperation Research Project</creatorcontrib><title>Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor</title><title>Chemical & pharmaceutical bulletin</title><addtitle>Chem. Pharm. Bull.</addtitle><description>Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.</description><subject>Animals</subject><subject>Avoidance behavior</subject><subject>Avoidance Learning - drug effects</subject><subject>Binding Sites</subject><subject>Brain</subject><subject>conditioned avoidance response (CAR)</subject><subject>Conditioning</subject><subject>Crystallography, X-Ray</subject><subject>Cyclic AMP</subject><subject>Cyclic GMP</subject><subject>Drug Evaluation, Preclinical</subject><subject>Erectile dysfunction</subject><subject>Homology</subject><subject>Hydrolase</subject><subject>Inhibitors</subject><subject>Inhibitory Concentration 50</subject><subject>Mental disorders</subject><subject>Molecular Dynamics Simulation</subject><subject>Neostriatum</subject><subject>Neurons</subject><subject>Optimization</subject><subject>Penetration</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Phosphodiesterase</subject><subject>phosphodiesterase (PDE) 10A</subject><subject>Phosphodiesterase Inhibitors - chemistry</subject><subject>Phosphodiesterase Inhibitors - metabolism</subject><subject>Phosphodiesterase Inhibitors - pharmacology</subject><subject>Phosphoric Diester Hydrolases - chemistry</subject><subject>Phosphoric Diester Hydrolases - metabolism</subject><subject>Psychosis</subject><subject>pyrimidine</subject><subject>Pyrimidines - chemical synthesis</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Quinoxaline</subject><subject>Quinoxalines</subject><subject>Quinoxalines - chemical synthesis</subject><subject>Quinoxalines - chemistry</subject><subject>Quinoxalines - pharmacology</subject><subject>Rats</subject><subject>Rodents</subject><subject>Schizophrenia</subject><subject>Signs and symptoms</subject><subject>Spiny neurons</subject><subject>Stilbene</subject><subject>Structure-Activity Relationship</subject><subject>Tetrahydro-2H-pyran</subject><issn>0009-2363</issn><issn>1347-5223</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkl9v0zAUxSMEYmXwyCuKxEv34OF_sZPHqevWSRMgAU8IWa7jLK7cuLOTinwuviA37egkXmxL5-d7j-9xlr0n-JJQXn4yu_WlIRJhLEv2IpsRxiUqKGUvsxnGuEKUCXaWvUlpgzEtsGSvszNa8YrQopxlf65dMmFv45iHJqfo53x5gSiaS3TjhxADYmhr-3b0j4Prwm_tXQfy6C_2rhv9LyTQbowxeFeDQEBAn9G8t33U7VjDdbqaAN0hPl2Co9seUI701nU2X02UaX2Irra5TrnOV-6h9WP-zXprere3-dfrJcFX-V3XurXrQ3ybvWq0T_bd036e_bhZfl-s0P2X27vF1T0yEtMeWVJwSquK17zRuqpNwQQlpGKYc2wsbkzBSy3qqqywrAQvCMHMlriRa4YNoew8mx_r7mJ4HGzq1RaGZb3XnQ1DUhTGWwhBqQD043_oJgyxA3cKoiClxAIzoNCRMjGkFG2jdjAPHUdFsJrSVJCmgjTVIU3gPzxVHdZbW5_of_EBcHsEQHVG-9BBPva5t0nStHbrwCopoagAF7BVClMOB_gODDMp-fTWxbHSJvX6wZ5a6dg74-3BmBCKTcvJ4LPa6qhsx_4CRorGhg</recordid><startdate>2018</startdate><enddate>2018</enddate><creator>Kadoh, Yoichi</creator><creator>Miyoshi, Haruko</creator><creator>Matsumura, Takehiko</creator><creator>Tanaka, Yoshihito</creator><creator>Hongu, Mitsuya</creator><creator>Kimura, Mayumi</creator><creator>Takedomi, Kei</creator><creator>Omori, Kenji</creator><creator>Kotera, Jun</creator><creator>Sasaki, Takashi</creator><creator>Kobayashi, Tamaki</creator><creator>Taniguchi, Hiroyuki</creator><creator>Watanabe, Yumi</creator><creator>Kojima, Koki</creator><creator>Sakamoto, Toshiaki</creator><creator>Himiyama, Toshiyuki</creator><creator>Kawanishi, Eiji</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>2018</creationdate><title>Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor</title><author>Kadoh, Yoichi ; Miyoshi, Haruko ; Matsumura, Takehiko ; Tanaka, Yoshihito ; Hongu, Mitsuya ; Kimura, Mayumi ; Takedomi, Kei ; Omori, Kenji ; Kotera, Jun ; Sasaki, Takashi ; Kobayashi, Tamaki ; Taniguchi, Hiroyuki ; Watanabe, Yumi ; Kojima, Koki ; Sakamoto, Toshiaki ; Himiyama, Toshiyuki ; Kawanishi, Eiji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c702t-e15422994d4faa9dc536211930440ce0fc548a6d9890796451103e80f7b30c123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Avoidance behavior</topic><topic>Avoidance Learning - drug effects</topic><topic>Binding Sites</topic><topic>Brain</topic><topic>conditioned avoidance response (CAR)</topic><topic>Conditioning</topic><topic>Crystallography, X-Ray</topic><topic>Cyclic AMP</topic><topic>Cyclic GMP</topic><topic>Drug Evaluation, Preclinical</topic><topic>Erectile dysfunction</topic><topic>Homology</topic><topic>Hydrolase</topic><topic>Inhibitors</topic><topic>Inhibitory Concentration 50</topic><topic>Mental disorders</topic><topic>Molecular Dynamics Simulation</topic><topic>Neostriatum</topic><topic>Neurons</topic><topic>Optimization</topic><topic>Penetration</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Phosphodiesterase</topic><topic>phosphodiesterase (PDE) 10A</topic><topic>Phosphodiesterase Inhibitors - chemistry</topic><topic>Phosphodiesterase Inhibitors - metabolism</topic><topic>Phosphodiesterase Inhibitors - pharmacology</topic><topic>Phosphoric Diester Hydrolases - chemistry</topic><topic>Phosphoric Diester Hydrolases - metabolism</topic><topic>Psychosis</topic><topic>pyrimidine</topic><topic>Pyrimidines - chemical synthesis</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Quinoxaline</topic><topic>Quinoxalines</topic><topic>Quinoxalines - chemical synthesis</topic><topic>Quinoxalines - chemistry</topic><topic>Quinoxalines - pharmacology</topic><topic>Rats</topic><topic>Rodents</topic><topic>Schizophrenia</topic><topic>Signs and symptoms</topic><topic>Spiny neurons</topic><topic>Stilbene</topic><topic>Structure-Activity Relationship</topic><topic>Tetrahydro-2H-pyran</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kadoh, Yoichi</creatorcontrib><creatorcontrib>Miyoshi, Haruko</creatorcontrib><creatorcontrib>Matsumura, Takehiko</creatorcontrib><creatorcontrib>Tanaka, Yoshihito</creatorcontrib><creatorcontrib>Hongu, Mitsuya</creatorcontrib><creatorcontrib>Kimura, Mayumi</creatorcontrib><creatorcontrib>Takedomi, Kei</creatorcontrib><creatorcontrib>Omori, Kenji</creatorcontrib><creatorcontrib>Kotera, Jun</creatorcontrib><creatorcontrib>Sasaki, Takashi</creatorcontrib><creatorcontrib>Kobayashi, Tamaki</creatorcontrib><creatorcontrib>Taniguchi, Hiroyuki</creatorcontrib><creatorcontrib>Watanabe, Yumi</creatorcontrib><creatorcontrib>Kojima, Koki</creatorcontrib><creatorcontrib>Sakamoto, Toshiaki</creatorcontrib><creatorcontrib>Himiyama, Toshiyuki</creatorcontrib><creatorcontrib>Kawanishi, Eiji</creatorcontrib><creatorcontrib>Nagoya University</creatorcontrib><creatorcontrib>Laboratory of Target and Drug Discovery</creatorcontrib><creatorcontrib>bMitsubishi Tanabe Pharma Corporation</creatorcontrib><creatorcontrib>aMitsubishi Tanabe Pharma Corporation</creatorcontrib><creatorcontrib>Graduate School of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>cIndustry and Academia Cooperation Research Project</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>Kadoh, Yoichi</au><au>Miyoshi, Haruko</au><au>Matsumura, Takehiko</au><au>Tanaka, Yoshihito</au><au>Hongu, Mitsuya</au><au>Kimura, Mayumi</au><au>Takedomi, Kei</au><au>Omori, Kenji</au><au>Kotera, Jun</au><au>Sasaki, Takashi</au><au>Kobayashi, Tamaki</au><au>Taniguchi, Hiroyuki</au><au>Watanabe, Yumi</au><au>Kojima, Koki</au><au>Sakamoto, Toshiaki</au><au>Himiyama, Toshiyuki</au><au>Kawanishi, Eiji</au><aucorp>Nagoya University</aucorp><aucorp>Laboratory of Target and Drug Discovery</aucorp><aucorp>bMitsubishi Tanabe Pharma Corporation</aucorp><aucorp>aMitsubishi Tanabe Pharma Corporation</aucorp><aucorp>Graduate School of Pharmaceutical Sciences</aucorp><aucorp>cIndustry and Academia Cooperation Research Project</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor</atitle><jtitle>Chemical & pharmaceutical bulletin</jtitle><addtitle>Chem. Pharm. Bull.</addtitle><date>2018</date><risdate>2018</risdate><volume>66</volume><issue>3</issue><spage>243</spage><epage>250</epage><pages>243-250</pages><issn>0009-2363</issn><eissn>1347-5223</eissn><abstract>Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5. We transformed the afforded derivatives, which had weak inhibitory activity against PDE10A, and discovered stilbene as a PDE10A inhibitor. Brain penetration of this compound was improved by further conversion of N-containing heterocycles and their substituents. The afforded dimethylaminopyrimidine was effective for rat conditioned avoidance response (CAR) test; however, it did not exhibit good brain penetration. We performed in-depth optimization focusing on substituents of the quinoxaline ring, and produced 3-methyl-7-fluoro quinoxaline. This compound was the most effective in rat CAR test due to its strong PDE10A inhibitory activity and good pharmacokinetics.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>29491258</pmid><doi>10.1248/cpb.c17-00783</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-2363 |
| ispartof | Chemical and Pharmaceutical Bulletin, 2018/03/01, Vol.66(3), pp.243-250 |
| issn | 0009-2363 1347-5223 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2009566226 |
| source | J-STAGE Free; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Animals Avoidance behavior Avoidance Learning - drug effects Binding Sites Brain conditioned avoidance response (CAR) Conditioning Crystallography, X-Ray Cyclic AMP Cyclic GMP Drug Evaluation, Preclinical Erectile dysfunction Homology Hydrolase Inhibitors Inhibitory Concentration 50 Mental disorders Molecular Dynamics Simulation Neostriatum Neurons Optimization Penetration Pharmacokinetics Pharmacology Phosphodiesterase phosphodiesterase (PDE) 10A Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - metabolism Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - chemistry Phosphoric Diester Hydrolases - metabolism Psychosis pyrimidine Pyrimidines - chemical synthesis Pyrimidines - chemistry Pyrimidines - pharmacology Quinoxaline Quinoxalines Quinoxalines - chemical synthesis Quinoxalines - chemistry Quinoxalines - pharmacology Rats Rodents Schizophrenia Signs and symptoms Spiny neurons Stilbene Structure-Activity Relationship Tetrahydro-2H-pyran |
| title | Discovery of 2-[(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl]-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine Hydrochloride as a Highly Selective PDE10A Inhibitor |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-20T13%3A07%3A39IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%202-%5B(E)-2-(7-Fluoro-3-methylquinoxalin-2-yl)vinyl%5D-6-pyrrolidin-1-yl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine%20Hydrochloride%20as%20a%20Highly%20Selective%20PDE10A%20Inhibitor&rft.jtitle=Chemical%20&%20pharmaceutical%20bulletin&rft.au=Kadoh,%20Yoichi&rft.aucorp=Nagoya%20University&rft.date=2018&rft.volume=66&rft.issue=3&rft.spage=243&rft.epage=250&rft.pages=243-250&rft.issn=0009-2363&rft.eissn=1347-5223&rft_id=info:doi/10.1248/cpb.c17-00783&rft_dat=%3Cproquest_cross%3E2009566226%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2231870603&rft_id=info:pmid/29491258&rfr_iscdi=true |