Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor‑2 Positive Allosteric Modulators against Migraine
Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyra...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-06, Vol.64 (12), p.8607-8620 |
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| container_title | Journal of medicinal chemistry |
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| creator | Szabó, György Erdélyi, Péter Kolok, Sándor Vastag, Mónika Halász, Attila S Kis-Varga, Istvánné Lévay, György I Béni, Zoltán Kóti, János Greiner, István Keserű, György M |
| description | Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead (34) with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound 34 showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs. |
| doi_str_mv | 10.1021/acs.jmedchem.1c00563 |
| format | Article |
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Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead (34) with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound 34 showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.1c00563</identifier><identifier>PMID: 34080424</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Benzimidazoles - chemical synthesis ; Benzimidazoles - pharmacokinetics ; Benzimidazoles - therapeutic use ; Excitatory Amino Acid Agonists - chemical synthesis ; Excitatory Amino Acid Agonists - pharmacokinetics ; Excitatory Amino Acid Agonists - therapeutic use ; Male ; Migraine Disorders - drug therapy ; Molecular Structure ; Proof of Concept Study ; Pyrazines - chemical synthesis ; Pyrazines - pharmacokinetics ; Pyrazines - therapeutic use ; Rats ; Rats, Wistar ; Receptors, Metabotropic Glutamate - agonists ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2021-06, Vol.64 (12), p.8607-8620</ispartof><rights>2021 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-7c3bce2b14fd31f7605bd5c4d9da7a7444584406b336f8d246e43d94d599abdf3</citedby><cites>FETCH-LOGICAL-a348t-7c3bce2b14fd31f7605bd5c4d9da7a7444584406b336f8d246e43d94d599abdf3</cites><orcidid>0000-0002-5336-2828 ; 0000-0003-1039-7809 ; 0000-0002-9255-4486</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c00563$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c00563$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34080424$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Szabó, György</creatorcontrib><creatorcontrib>Erdélyi, Péter</creatorcontrib><creatorcontrib>Kolok, Sándor</creatorcontrib><creatorcontrib>Vastag, Mónika</creatorcontrib><creatorcontrib>Halász, Attila S</creatorcontrib><creatorcontrib>Kis-Varga, Istvánné</creatorcontrib><creatorcontrib>Lévay, György I</creatorcontrib><creatorcontrib>Béni, Zoltán</creatorcontrib><creatorcontrib>Kóti, János</creatorcontrib><creatorcontrib>Greiner, István</creatorcontrib><creatorcontrib>Keserű, György M</creatorcontrib><title>Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor‑2 Positive Allosteric Modulators against Migraine</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead (34) with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound 34 showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.</description><subject>Animals</subject><subject>Benzimidazoles - chemical synthesis</subject><subject>Benzimidazoles - pharmacokinetics</subject><subject>Benzimidazoles - therapeutic use</subject><subject>Excitatory Amino Acid Agonists - chemical synthesis</subject><subject>Excitatory Amino Acid Agonists - pharmacokinetics</subject><subject>Excitatory Amino Acid Agonists - therapeutic use</subject><subject>Male</subject><subject>Migraine Disorders - drug therapy</subject><subject>Molecular Structure</subject><subject>Proof of Concept Study</subject><subject>Pyrazines - chemical synthesis</subject><subject>Pyrazines - pharmacokinetics</subject><subject>Pyrazines - therapeutic use</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Receptors, Metabotropic Glutamate - agonists</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtOwzAQhi0EgvK4AUK-QIpfSdslrwISFQjBOprYk2KUxJHtIrUrrsCGA3ISDAWWrGak-f5fmo-QQ86GnAl-DDoMn1s0-gnbIdeM5YXcIAOeC5apMVObZMCYEJkohNwhuyE8M8YkF3Kb7EjFEiHUgLxPPcxb7GJ2CgENve2jbe0KonUddTU9t09L412_9LCynctOsVslwMDKNa7DQCHQGUaoXEyU1fSyWURoISK9R419dP7j9U3QOxdstC9IT5rGhYg-oTNnFg0kIrXMwXYh0pmd-7ThPtmqoQl48DP3yOP04uHsKru5vbw-O7nJQKpxzEZaVhpFxVVtJK9HBcsrk2tlJgZGMFJK5WOlWFFJWdRjI1SBSpqJMvlkApWp5R5R617tXQge67L3tgW_LDkrvzSXSXP5q7n80ZxiR-tYv6jS7S_06zUBbA18x93Cd-mL_zs_AW0Ikl8</recordid><startdate>20210624</startdate><enddate>20210624</enddate><creator>Szabó, György</creator><creator>Erdélyi, Péter</creator><creator>Kolok, Sándor</creator><creator>Vastag, Mónika</creator><creator>Halász, Attila S</creator><creator>Kis-Varga, Istvánné</creator><creator>Lévay, György I</creator><creator>Béni, Zoltán</creator><creator>Kóti, János</creator><creator>Greiner, István</creator><creator>Keserű, György M</creator><general>American Chemical Society</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><orcidid>https://orcid.org/0000-0002-5336-2828</orcidid><orcidid>https://orcid.org/0000-0003-1039-7809</orcidid><orcidid>https://orcid.org/0000-0002-9255-4486</orcidid></search><sort><creationdate>20210624</creationdate><title>Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor‑2 Positive Allosteric Modulators against Migraine</title><author>Szabó, György ; Erdélyi, Péter ; Kolok, Sándor ; Vastag, Mónika ; Halász, Attila S ; Kis-Varga, Istvánné ; Lévay, György I ; Béni, Zoltán ; Kóti, János ; Greiner, István ; Keserű, György M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-7c3bce2b14fd31f7605bd5c4d9da7a7444584406b336f8d246e43d94d599abdf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Benzimidazoles - chemical synthesis</topic><topic>Benzimidazoles - pharmacokinetics</topic><topic>Benzimidazoles - therapeutic use</topic><topic>Excitatory Amino Acid Agonists - chemical synthesis</topic><topic>Excitatory Amino Acid Agonists - pharmacokinetics</topic><topic>Excitatory Amino Acid Agonists - therapeutic use</topic><topic>Male</topic><topic>Migraine Disorders - drug therapy</topic><topic>Molecular Structure</topic><topic>Proof of Concept Study</topic><topic>Pyrazines - chemical synthesis</topic><topic>Pyrazines - pharmacokinetics</topic><topic>Pyrazines - therapeutic use</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Receptors, Metabotropic Glutamate - agonists</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Szabó, György</creatorcontrib><creatorcontrib>Erdélyi, Péter</creatorcontrib><creatorcontrib>Kolok, Sándor</creatorcontrib><creatorcontrib>Vastag, Mónika</creatorcontrib><creatorcontrib>Halász, Attila S</creatorcontrib><creatorcontrib>Kis-Varga, Istvánné</creatorcontrib><creatorcontrib>Lévay, György I</creatorcontrib><creatorcontrib>Béni, Zoltán</creatorcontrib><creatorcontrib>Kóti, János</creatorcontrib><creatorcontrib>Greiner, István</creatorcontrib><creatorcontrib>Keserű, György M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Szabó, György</au><au>Erdélyi, Péter</au><au>Kolok, Sándor</au><au>Vastag, Mónika</au><au>Halász, Attila S</au><au>Kis-Varga, Istvánné</au><au>Lévay, György I</au><au>Béni, Zoltán</au><au>Kóti, János</au><au>Greiner, István</au><au>Keserű, György M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor‑2 Positive Allosteric Modulators against Migraine</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2021-06-24</date><risdate>2021</risdate><volume>64</volume><issue>12</issue><spage>8607</spage><epage>8620</epage><pages>8607-8620</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead (34) with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound 34 showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>34080424</pmid><doi>10.1021/acs.jmedchem.1c00563</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-5336-2828</orcidid><orcidid>https://orcid.org/0000-0003-1039-7809</orcidid><orcidid>https://orcid.org/0000-0002-9255-4486</orcidid></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2021-06, Vol.64 (12), p.8607-8620 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; American Chemical Society (ACS) Journals |
| subjects | Animals Benzimidazoles - chemical synthesis Benzimidazoles - pharmacokinetics Benzimidazoles - therapeutic use Excitatory Amino Acid Agonists - chemical synthesis Excitatory Amino Acid Agonists - pharmacokinetics Excitatory Amino Acid Agonists - therapeutic use Male Migraine Disorders - drug therapy Molecular Structure Proof of Concept Study Pyrazines - chemical synthesis Pyrazines - pharmacokinetics Pyrazines - therapeutic use Rats Rats, Wistar Receptors, Metabotropic Glutamate - agonists Structure-Activity Relationship |
| title | Fragment-Based Optimization of Dihydropyrazino-Benzimidazolones as Metabotropic Glutamate Receptor‑2 Positive Allosteric Modulators against Migraine |
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