Structure-Based Drug Discovery of N‑((R)‑3-(7-Methyl‑1H‑indazol-5-yl)-1-oxo-1-(((S)‑1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3‑d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine
Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compou...
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| Veröffentlicht in: | Journal of medicinal chemistry 2020-07, Vol.63 (14), p.7906-7920 |
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| creator | Bucknell, Sarah J Ator, Mark A Brown, Alastair J. H Brown, Jason Cansfield, Andrew D Cansfield, Julie E Christopher, John A Congreve, Miles Cseke, Gabriella Deflorian, Francesca Jones, Christopher R Mason, Jonathan S O’Brien, M. Alistair Ott, Gregory R Pickworth, Mark Southall, Stacey M |
| description | Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine. |
| doi_str_mv | 10.1021/acs.jmedchem.0c01003 |
| format | Article |
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H ; Brown, Jason ; Cansfield, Andrew D ; Cansfield, Julie E ; Christopher, John A ; Congreve, Miles ; Cseke, Gabriella ; Deflorian, Francesca ; Jones, Christopher R ; Mason, Jonathan S ; O’Brien, M. Alistair ; Ott, Gregory R ; Pickworth, Mark ; Southall, Stacey M</creator><creatorcontrib>Bucknell, Sarah J ; Ator, Mark A ; Brown, Alastair J. H ; Brown, Jason ; Cansfield, Andrew D ; Cansfield, Julie E ; Christopher, John A ; Congreve, Miles ; Cseke, Gabriella ; Deflorian, Francesca ; Jones, Christopher R ; Mason, Jonathan S ; O’Brien, M. Alistair ; Ott, Gregory R ; Pickworth, Mark ; Southall, Stacey M</creatorcontrib><description>Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c01003</identifier><identifier>PMID: 32558564</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Binding Sites ; Calcitonin Gene-Related Peptide Receptor Antagonists - chemical synthesis ; Calcitonin Gene-Related Peptide Receptor Antagonists - metabolism ; Calcitonin Gene-Related Peptide Receptor Antagonists - pharmacology ; Calcitonin Gene-Related Peptide Receptor Antagonists - toxicity ; Dogs ; Drug Design ; Humans ; Indazoles - chemical synthesis ; Indazoles - metabolism ; Indazoles - pharmacology ; Indazoles - toxicity ; Macaca fascicularis ; Migraine Disorders - drug therapy ; Molecular Docking Simulation ; Molecular Structure ; Rats ; Receptors, Calcitonin Gene-Related Peptide - metabolism ; Spiro Compounds - chemical synthesis ; Spiro Compounds - metabolism ; Spiro Compounds - pharmacology ; Spiro Compounds - toxicity ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2020-07, Vol.63 (14), p.7906-7920</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a418t-2838732310e1ace15d423a14f6fba4df96dcf09458ae7213b584c9c39224d2453</citedby><cites>FETCH-LOGICAL-a418t-2838732310e1ace15d423a14f6fba4df96dcf09458ae7213b584c9c39224d2453</cites><orcidid>0000-0002-8904-4645 ; 0000-0003-1913-0318 ; 0000-0002-6501-8899 ; 0000-0002-4844-1900</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.0c01003$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c01003$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32558564$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bucknell, Sarah J</creatorcontrib><creatorcontrib>Ator, Mark A</creatorcontrib><creatorcontrib>Brown, Alastair J. H</creatorcontrib><creatorcontrib>Brown, Jason</creatorcontrib><creatorcontrib>Cansfield, Andrew D</creatorcontrib><creatorcontrib>Cansfield, Julie E</creatorcontrib><creatorcontrib>Christopher, John A</creatorcontrib><creatorcontrib>Congreve, Miles</creatorcontrib><creatorcontrib>Cseke, Gabriella</creatorcontrib><creatorcontrib>Deflorian, Francesca</creatorcontrib><creatorcontrib>Jones, Christopher R</creatorcontrib><creatorcontrib>Mason, Jonathan S</creatorcontrib><creatorcontrib>O’Brien, M. Alistair</creatorcontrib><creatorcontrib>Ott, Gregory R</creatorcontrib><creatorcontrib>Pickworth, Mark</creatorcontrib><creatorcontrib>Southall, Stacey M</creatorcontrib><title>Structure-Based Drug Discovery of N‑((R)‑3-(7-Methyl‑1H‑indazol-5-yl)-1-oxo-1-(((S)‑1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3‑d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.</description><subject>Animals</subject><subject>Binding Sites</subject><subject>Calcitonin Gene-Related Peptide Receptor Antagonists - chemical synthesis</subject><subject>Calcitonin Gene-Related Peptide Receptor Antagonists - metabolism</subject><subject>Calcitonin Gene-Related Peptide Receptor Antagonists - pharmacology</subject><subject>Calcitonin Gene-Related Peptide Receptor Antagonists - toxicity</subject><subject>Dogs</subject><subject>Drug Design</subject><subject>Humans</subject><subject>Indazoles - chemical synthesis</subject><subject>Indazoles - metabolism</subject><subject>Indazoles - pharmacology</subject><subject>Indazoles - toxicity</subject><subject>Macaca fascicularis</subject><subject>Migraine Disorders - drug therapy</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Structure</subject><subject>Rats</subject><subject>Receptors, Calcitonin Gene-Related Peptide - metabolism</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - metabolism</subject><subject>Spiro Compounds - pharmacology</subject><subject>Spiro Compounds - toxicity</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9Ut1u0zAYDQjEyuANEMplKtXFf2lT7koHK1IHqCtXVRW5ttN5SuLIcaZlV3sFXoVH2pPwpe0muOHG_s7nc76TfDpB8I7gIcGUfBCyHl4XWskrXQyxxARj9jzokZhixBPMXwQ9jClFdETZSfC6rq8xMAhlr4ITRuM4iUe89-zm0rtG-sZp9EnUWoVnrtmFZ6aW9ka7NrRZ-O3h_lcULftwMRSN0YX2V20OiMzhMKUSdzZHMWrzPiLI3lo4oyi67AQHDLLKVNoZZUrEj8SIQ7f9q7eniDuAZA-drUSJaFeLwpT2nw6iD_e_D2ZQDPZImatWOVtXxtn1k6FGfMC7572ZXdMBgw9TmzUZsI297Qz1BiylcFuAhVE6jOarBaXxiPY_htNwJnJpvC1NGZ5rmLfUufCwqh-68h17qSVU1oXT0osd8GofZh2UjdfhymnhC136bpcXZucEGL4JXmYir_Xb430a_PzyeTWbo8X386-z6QIJThKPaMKSMaOMYE2E1CRWnDJBeDbKtoKrbDJSMsMTHidCjylh2zjhciLZhFKuKI_ZacAPcyXspXY6SytnCuHalOC0i1EKMUofY5QeYwSy9wdZ1Wzh7Un0mBsg4ANhL7eNK-Ev_j_zD9fZ30U</recordid><startdate>20200723</startdate><enddate>20200723</enddate><creator>Bucknell, Sarah J</creator><creator>Ator, Mark A</creator><creator>Brown, Alastair J. 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Alistair</creator><creator>Ott, Gregory R</creator><creator>Pickworth, Mark</creator><creator>Southall, Stacey 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/0000-0002-8904-4645</orcidid><orcidid>https://orcid.org/0000-0003-1913-0318</orcidid><orcidid>https://orcid.org/0000-0002-6501-8899</orcidid><orcidid>https://orcid.org/0000-0002-4844-1900</orcidid></search><sort><creationdate>20200723</creationdate><title>Structure-Based Drug Discovery of N‑((R)‑3-(7-Methyl‑1H‑indazol-5-yl)-1-oxo-1-(((S)‑1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3‑d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine</title><author>Bucknell, Sarah J ; Ator, Mark A ; Brown, Alastair J. H ; Brown, Jason ; Cansfield, Andrew D ; Cansfield, Julie E ; Christopher, John A ; Congreve, Miles ; Cseke, Gabriella ; Deflorian, Francesca ; Jones, Christopher R ; Mason, Jonathan S ; O’Brien, M. 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Alistair</creatorcontrib><creatorcontrib>Ott, Gregory R</creatorcontrib><creatorcontrib>Pickworth, Mark</creatorcontrib><creatorcontrib>Southall, Stacey 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>Bucknell, Sarah J</au><au>Ator, Mark A</au><au>Brown, Alastair J. H</au><au>Brown, Jason</au><au>Cansfield, Andrew D</au><au>Cansfield, Julie E</au><au>Christopher, John A</au><au>Congreve, Miles</au><au>Cseke, Gabriella</au><au>Deflorian, Francesca</au><au>Jones, Christopher R</au><au>Mason, Jonathan S</au><au>O’Brien, M. Alistair</au><au>Ott, Gregory R</au><au>Pickworth, Mark</au><au>Southall, Stacey M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Based Drug Discovery of N‑((R)‑3-(7-Methyl‑1H‑indazol-5-yl)-1-oxo-1-(((S)‑1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3‑d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-07-23</date><risdate>2020</risdate><volume>63</volume><issue>14</issue><spage>7906</spage><epage>7920</epage><pages>7906-7920</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Structure-based drug design enabled the discovery of 8, HTL22562, a calcitonin gene-related peptide (CGRP) receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at a 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable, and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g., subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being selected as a clinical candidate for acute treatment of migraine.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32558564</pmid><doi>10.1021/acs.jmedchem.0c01003</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-8904-4645</orcidid><orcidid>https://orcid.org/0000-0003-1913-0318</orcidid><orcidid>https://orcid.org/0000-0002-6501-8899</orcidid><orcidid>https://orcid.org/0000-0002-4844-1900</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2020-07, Vol.63 (14), p.7906-7920 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_acs_jmedchem_0c01003 |
| source | MEDLINE; ACS Publications |
| subjects | Animals Binding Sites Calcitonin Gene-Related Peptide Receptor Antagonists - chemical synthesis Calcitonin Gene-Related Peptide Receptor Antagonists - metabolism Calcitonin Gene-Related Peptide Receptor Antagonists - pharmacology Calcitonin Gene-Related Peptide Receptor Antagonists - toxicity Dogs Drug Design Humans Indazoles - chemical synthesis Indazoles - metabolism Indazoles - pharmacology Indazoles - toxicity Macaca fascicularis Migraine Disorders - drug therapy Molecular Docking Simulation Molecular Structure Rats Receptors, Calcitonin Gene-Related Peptide - metabolism Spiro Compounds - chemical synthesis Spiro Compounds - metabolism Spiro Compounds - pharmacology Spiro Compounds - toxicity Structure-Activity Relationship |
| title | Structure-Based Drug Discovery of N‑((R)‑3-(7-Methyl‑1H‑indazol-5-yl)-1-oxo-1-(((S)‑1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2′-oxo-1′,2′-dihydrospiro[piperidine-4,4′-pyrido[2,3‑d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine |
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