Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M4 muscarinic acetylcholine receptor
[Display omitted] In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generati...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2022-01, Vol.56, p.128479-128479, Article 128479 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Bender, Aaron M. Carter, Trever R. Spock, Matthew Rodriguez, Alice L. Dickerson, Jonathan W. Rook, Jerri M. Chang, Sichen Qi, Aidong Presley, Christopher C. Engers, Darren W. Harp, Joel M. Bridges, Thomas M. Niswender, Colleen M. Conn, P. Jeffrey Lindsley, Craig W. |
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In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure–activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration. |
| doi_str_mv | 10.1016/j.bmcl.2021.128479 |
| format | Article |
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In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure–activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2021.128479</identifier><language>eng</language><publisher>Elsevier Ltd</publisher><subject>cytochrome P450 ; Deuterium ; muscarinic acetylcholine receptor M4 ; SAR ; Spirocycle</subject><ispartof>Bioorganic & medicinal chemistry letters, 2022-01, Vol.56, p.128479-128479, Article 128479</ispartof><rights>2021 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c333t-814497d86f0f2a14e8d925abe4937eb4f42f08d4052c09e695443000e37bca153</citedby><cites>FETCH-LOGICAL-c333t-814497d86f0f2a14e8d925abe4937eb4f42f08d4052c09e695443000e37bca153</cites><orcidid>0000-0002-5244-5103 ; 0000-0002-4641-4597 ; 0000-0001-7263-3788 ; 0000-0002-9116-5606 ; 0000-0003-0432-1648 ; 0000-0001-5938-4043</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2021.128479$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids></links><search><creatorcontrib>Bender, Aaron M.</creatorcontrib><creatorcontrib>Carter, Trever R.</creatorcontrib><creatorcontrib>Spock, Matthew</creatorcontrib><creatorcontrib>Rodriguez, Alice L.</creatorcontrib><creatorcontrib>Dickerson, Jonathan W.</creatorcontrib><creatorcontrib>Rook, Jerri M.</creatorcontrib><creatorcontrib>Chang, Sichen</creatorcontrib><creatorcontrib>Qi, Aidong</creatorcontrib><creatorcontrib>Presley, Christopher C.</creatorcontrib><creatorcontrib>Engers, Darren W.</creatorcontrib><creatorcontrib>Harp, Joel M.</creatorcontrib><creatorcontrib>Bridges, Thomas M.</creatorcontrib><creatorcontrib>Niswender, Colleen M.</creatorcontrib><creatorcontrib>Conn, P. Jeffrey</creatorcontrib><creatorcontrib>Lindsley, Craig W.</creatorcontrib><title>Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M4 muscarinic acetylcholine receptor</title><title>Bioorganic & medicinal chemistry letters</title><description>[Display omitted]
In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure–activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.</description><subject>cytochrome P450</subject><subject>Deuterium</subject><subject>muscarinic acetylcholine receptor M4</subject><subject>SAR</subject><subject>Spirocycle</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kE2LFDEQhoMoOK7-AU85euk2X_0R8CKLX7CLBxUEkZCprnYy9CRtKrMw-yf8y2Ycz3sqqqinivdh7KUUrRSyf71vtwdYWiWUbKUazWAfsY00vWm0Ed1jthG2F81ozfen7BnRXghphDEb9ufLKZYdUiDu48Rh57OHgjnc-xJS5Gmus5D9wvvG33taQ04_VNv9TFB8xEoRX1PBWP7xhAtCCXdYu-J_pRio0PlI_cFvDT8cCXwOMQD3gOW0wC4tISLPCLiWlJ-zJ7NfCF_8r1fs2_t3X68_NjefP3y6fnvTgNa6NKM0xg7T2M9iVl4aHCerOr9FY_WAWzMbNYtxqtkVCIu97YzRQgjUwxa87PQVe3W5u-b0-4hU3CEQ4LLUUOlITvVVzyB0b-uquqxCTkQZZ7fmcPD55KRwZ_tu78723dm-u9iv0JsLhDXEXcDsCAJGwCnUqMVNKTyE_wUlypAR</recordid><startdate>20220115</startdate><enddate>20220115</enddate><creator>Bender, Aaron M.</creator><creator>Carter, Trever R.</creator><creator>Spock, Matthew</creator><creator>Rodriguez, Alice L.</creator><creator>Dickerson, Jonathan W.</creator><creator>Rook, Jerri M.</creator><creator>Chang, Sichen</creator><creator>Qi, Aidong</creator><creator>Presley, Christopher C.</creator><creator>Engers, Darren W.</creator><creator>Harp, Joel M.</creator><creator>Bridges, Thomas M.</creator><creator>Niswender, Colleen M.</creator><creator>Conn, P. 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Jeffrey</creatorcontrib><creatorcontrib>Lindsley, Craig W.</creatorcontrib><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bender, Aaron M.</au><au>Carter, Trever R.</au><au>Spock, Matthew</au><au>Rodriguez, Alice L.</au><au>Dickerson, Jonathan W.</au><au>Rook, Jerri M.</au><au>Chang, Sichen</au><au>Qi, Aidong</au><au>Presley, Christopher C.</au><au>Engers, Darren W.</au><au>Harp, Joel M.</au><au>Bridges, Thomas M.</au><au>Niswender, Colleen M.</au><au>Conn, P. Jeffrey</au><au>Lindsley, Craig W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M4 muscarinic acetylcholine receptor</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><date>2022-01-15</date><risdate>2022</risdate><volume>56</volume><spage>128479</spage><epage>128479</epage><pages>128479-128479</pages><artnum>128479</artnum><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure–activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.</abstract><pub>Elsevier Ltd</pub><doi>10.1016/j.bmcl.2021.128479</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-5244-5103</orcidid><orcidid>https://orcid.org/0000-0002-4641-4597</orcidid><orcidid>https://orcid.org/0000-0001-7263-3788</orcidid><orcidid>https://orcid.org/0000-0002-9116-5606</orcidid><orcidid>https://orcid.org/0000-0003-0432-1648</orcidid><orcidid>https://orcid.org/0000-0001-5938-4043</orcidid></addata></record> |
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| source | Elsevier ScienceDirect Journals |
| subjects | cytochrome P450 Deuterium muscarinic acetylcholine receptor M4 SAR Spirocycle |
| title | Synthesis and characterization of chiral 6-azaspiro[2.5]octanes as potent and selective antagonists of the M4 muscarinic acetylcholine receptor |
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