1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectr...
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| Veröffentlicht in: | Journal of medicinal chemistry 2012-04, Vol.55 (7), p.2945-2959 |
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| creator | Vachal, Petr Miao, Shouwu Pierce, Joan M Guiadeen, Deodial Colandrea, Vincent J Wyvratt, Matthew J Salowe, Scott P Sonatore, Lisa M Milligan, James A Hajdu, Richard Gollapudi, Anantha Keohane, Carol A Lingham, Russell B Mandala, Suzanne M DeMartino, Julie A Tong, Xinchun Wolff, Michael Steinhuebel, Dietrich Kieczykowski, Gerard R Fleitz, Fred J Chapman, Kevin Athanasopoulos, John Adam, Gregory Akyuz, Can D Jena, Dhirendra K Lusen, Jeffrey W Meng, Juncai Stein, Benjamin D Xia, Lei Sherer, Edward C Hale, Jeffrey J |
| description | The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C–N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1–3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia. |
| doi_str_mv | 10.1021/jm201542d |
| format | Article |
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The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C–N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1–3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm201542d</identifier><identifier>PMID: 22364528</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Anemia - drug therapy ; Animals ; Aza Compounds - chemical synthesis ; Aza Compounds - pharmacokinetics ; Aza Compounds - pharmacology ; Dogs ; ERG1 Potassium Channel ; Erythropoietin - biosynthesis ; Ether-A-Go-Go Potassium Channels - metabolism ; High-Throughput Screening Assays ; Humans ; Hydantoins - chemical synthesis ; Hydantoins - pharmacokinetics ; Hydantoins - pharmacology ; Hypoxia-Inducible Factor 1 - metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases ; Indoles - chemical synthesis ; Indoles - pharmacokinetics ; Indoles - pharmacology ; Liver - drug effects ; Liver - enzymology ; Macaca mulatta ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Procollagen-Proline Dioxygenase - antagonists & inhibitors ; Protein Binding ; Rats ; Spiro Compounds - chemical synthesis ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - pharmacology ; Structure-Activity Relationship ; Up-Regulation</subject><ispartof>Journal of medicinal chemistry, 2012-04, Vol.55 (7), p.2945-2959</ispartof><rights>Copyright © 2012 American Chemical Society</rights><rights>2012 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-feb35299bd691b904da70796efba8e2a2837e20e0bd467ecfc17fbb84f03e0523</citedby><cites>FETCH-LOGICAL-a315t-feb35299bd691b904da70796efba8e2a2837e20e0bd467ecfc17fbb84f03e0523</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm201542d$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm201542d$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2751,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22364528$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vachal, Petr</creatorcontrib><creatorcontrib>Miao, Shouwu</creatorcontrib><creatorcontrib>Pierce, Joan M</creatorcontrib><creatorcontrib>Guiadeen, Deodial</creatorcontrib><creatorcontrib>Colandrea, Vincent J</creatorcontrib><creatorcontrib>Wyvratt, Matthew J</creatorcontrib><creatorcontrib>Salowe, Scott P</creatorcontrib><creatorcontrib>Sonatore, Lisa M</creatorcontrib><creatorcontrib>Milligan, James A</creatorcontrib><creatorcontrib>Hajdu, Richard</creatorcontrib><creatorcontrib>Gollapudi, Anantha</creatorcontrib><creatorcontrib>Keohane, Carol A</creatorcontrib><creatorcontrib>Lingham, Russell B</creatorcontrib><creatorcontrib>Mandala, Suzanne M</creatorcontrib><creatorcontrib>DeMartino, Julie A</creatorcontrib><creatorcontrib>Tong, Xinchun</creatorcontrib><creatorcontrib>Wolff, Michael</creatorcontrib><creatorcontrib>Steinhuebel, Dietrich</creatorcontrib><creatorcontrib>Kieczykowski, Gerard R</creatorcontrib><creatorcontrib>Fleitz, Fred J</creatorcontrib><creatorcontrib>Chapman, Kevin</creatorcontrib><creatorcontrib>Athanasopoulos, John</creatorcontrib><creatorcontrib>Adam, Gregory</creatorcontrib><creatorcontrib>Akyuz, Can D</creatorcontrib><creatorcontrib>Jena, Dhirendra K</creatorcontrib><creatorcontrib>Lusen, Jeffrey W</creatorcontrib><creatorcontrib>Meng, Juncai</creatorcontrib><creatorcontrib>Stein, Benjamin D</creatorcontrib><creatorcontrib>Xia, Lei</creatorcontrib><creatorcontrib>Sherer, Edward C</creatorcontrib><creatorcontrib>Hale, Jeffrey J</creatorcontrib><title>1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C–N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1–3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.</description><subject>Anemia - drug therapy</subject><subject>Animals</subject><subject>Aza Compounds - chemical synthesis</subject><subject>Aza Compounds - pharmacokinetics</subject><subject>Aza Compounds - pharmacology</subject><subject>Dogs</subject><subject>ERG1 Potassium Channel</subject><subject>Erythropoietin - biosynthesis</subject><subject>Ether-A-Go-Go Potassium Channels - metabolism</subject><subject>High-Throughput Screening Assays</subject><subject>Humans</subject><subject>Hydantoins - chemical synthesis</subject><subject>Hydantoins - pharmacokinetics</subject><subject>Hydantoins - pharmacology</subject><subject>Hypoxia-Inducible Factor 1 - metabolism</subject><subject>Hypoxia-Inducible Factor-Proline Dioxygenases</subject><subject>Indoles - chemical synthesis</subject><subject>Indoles - pharmacokinetics</subject><subject>Indoles - pharmacology</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Macaca mulatta</subject><subject>Mass Spectrometry</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Procollagen-Proline Dioxygenase - antagonists & inhibitors</subject><subject>Protein Binding</subject><subject>Rats</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - pharmacology</subject><subject>Structure-Activity Relationship</subject><subject>Up-Regulation</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc1qFEEUhQtRzBhd-AJSGyGBqVh__bcMMeMMBJzFuBJp6ucWqaG7a6zqhkxWvoPPkBfLk1jjxKxcXe49HwfuOQi9Z_SCUc4-bXtOWSG5fYFmrOCUyJrKl2hGKeeEl1ycoDcpbSmlgnHxGp1wLkpZ8HqGHthczGuyiV7dq7TzMXyXF8UPC0YNQPhcEuvDAAmrhK-d80YZH6aE12ogq-HWaz-GmHBweLnfhTuv8tVOxusO8EKZLOJ1DN2-y7qN4W7fqQSYPf76LfDZcrXA6-Xnv9s5dpkdbwFvIqixh2E8uF4O0Hv1Fr1yqkvw7mmeom-L683Vktx8_bK6urwhSrBiJA60KHjTaFs2TDdUWlXRqinBaVUDV7wWFXAKVFtZVmCcYZXTupaOCqAFF6fo7Oi7i-HnBGlse58MdF0OI3_dshyhpIUQB_T8iJoYUorg2l30vYr7DLWHVtrnVjL74cl20j3YZ_JfDRn4eASUSe02THHIX_7H6A_LWZP1</recordid><startdate>20120412</startdate><enddate>20120412</enddate><creator>Vachal, Petr</creator><creator>Miao, Shouwu</creator><creator>Pierce, Joan M</creator><creator>Guiadeen, Deodial</creator><creator>Colandrea, Vincent J</creator><creator>Wyvratt, Matthew J</creator><creator>Salowe, Scott P</creator><creator>Sonatore, Lisa M</creator><creator>Milligan, James A</creator><creator>Hajdu, Richard</creator><creator>Gollapudi, Anantha</creator><creator>Keohane, Carol A</creator><creator>Lingham, Russell B</creator><creator>Mandala, Suzanne M</creator><creator>DeMartino, Julie A</creator><creator>Tong, Xinchun</creator><creator>Wolff, Michael</creator><creator>Steinhuebel, Dietrich</creator><creator>Kieczykowski, Gerard R</creator><creator>Fleitz, Fred J</creator><creator>Chapman, Kevin</creator><creator>Athanasopoulos, John</creator><creator>Adam, Gregory</creator><creator>Akyuz, Can D</creator><creator>Jena, Dhirendra K</creator><creator>Lusen, Jeffrey W</creator><creator>Meng, Juncai</creator><creator>Stein, Benjamin D</creator><creator>Xia, Lei</creator><creator>Sherer, Edward C</creator><creator>Hale, Jeffrey J</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><scope>7X8</scope></search><sort><creationdate>20120412</creationdate><title>1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia</title><author>Vachal, Petr ; Miao, Shouwu ; Pierce, Joan M ; Guiadeen, Deodial ; Colandrea, Vincent J ; Wyvratt, Matthew J ; Salowe, Scott P ; Sonatore, Lisa M ; Milligan, James A ; Hajdu, Richard ; Gollapudi, Anantha ; Keohane, Carol A ; Lingham, Russell B ; Mandala, Suzanne M ; DeMartino, Julie A ; Tong, Xinchun ; Wolff, Michael ; Steinhuebel, Dietrich ; Kieczykowski, Gerard R ; Fleitz, Fred J ; Chapman, Kevin ; Athanasopoulos, John ; Adam, Gregory ; Akyuz, Can D ; Jena, Dhirendra K ; Lusen, Jeffrey W ; Meng, Juncai ; Stein, Benjamin D ; Xia, Lei ; Sherer, Edward C ; Hale, Jeffrey J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-feb35299bd691b904da70796efba8e2a2837e20e0bd467ecfc17fbb84f03e0523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Anemia - drug therapy</topic><topic>Animals</topic><topic>Aza Compounds - chemical synthesis</topic><topic>Aza Compounds - pharmacokinetics</topic><topic>Aza Compounds - pharmacology</topic><topic>Dogs</topic><topic>ERG1 Potassium Channel</topic><topic>Erythropoietin - biosynthesis</topic><topic>Ether-A-Go-Go Potassium Channels - metabolism</topic><topic>High-Throughput Screening Assays</topic><topic>Humans</topic><topic>Hydantoins - chemical synthesis</topic><topic>Hydantoins - pharmacokinetics</topic><topic>Hydantoins - pharmacology</topic><topic>Hypoxia-Inducible Factor 1 - metabolism</topic><topic>Hypoxia-Inducible Factor-Proline Dioxygenases</topic><topic>Indoles - chemical synthesis</topic><topic>Indoles - pharmacokinetics</topic><topic>Indoles - pharmacology</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Macaca mulatta</topic><topic>Mass Spectrometry</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Procollagen-Proline Dioxygenase - antagonists & inhibitors</topic><topic>Protein Binding</topic><topic>Rats</topic><topic>Spiro Compounds - 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Med. Chem</addtitle><date>2012-04-12</date><risdate>2012</risdate><volume>55</volume><issue>7</issue><spage>2945</spage><epage>2959</epage><pages>2945-2959</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C–N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1–3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>22364528</pmid><doi>10.1021/jm201542d</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2012-04, Vol.55 (7), p.2945-2959 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1000405332 |
| source | MEDLINE; ACS Publications |
| subjects | Anemia - drug therapy Animals Aza Compounds - chemical synthesis Aza Compounds - pharmacokinetics Aza Compounds - pharmacology Dogs ERG1 Potassium Channel Erythropoietin - biosynthesis Ether-A-Go-Go Potassium Channels - metabolism High-Throughput Screening Assays Humans Hydantoins - chemical synthesis Hydantoins - pharmacokinetics Hydantoins - pharmacology Hypoxia-Inducible Factor 1 - metabolism Hypoxia-Inducible Factor-Proline Dioxygenases Indoles - chemical synthesis Indoles - pharmacokinetics Indoles - pharmacology Liver - drug effects Liver - enzymology Macaca mulatta Mass Spectrometry Mice Mice, Inbred C57BL Procollagen-Proline Dioxygenase - antagonists & inhibitors Protein Binding Rats Spiro Compounds - chemical synthesis Spiro Compounds - pharmacokinetics Spiro Compounds - pharmacology Structure-Activity Relationship Up-Regulation |
| title | 1,3,8-Triazaspiro[4.5]decane-2,4-diones as Efficacious Pan-Inhibitors of Hypoxia-Inducible Factor Prolyl Hydroxylase 1–3 (HIF PHD1–3) for the Treatment of Anemia |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T01%3A40%3A11IST&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=1,3,8-Triazaspiro%5B4.5%5Ddecane-2,4-diones%20as%20Efficacious%20Pan-Inhibitors%20of%20Hypoxia-Inducible%20Factor%20Prolyl%20Hydroxylase%201%E2%80%933%20(HIF%20PHD1%E2%80%933)%20for%20the%20Treatment%20of%20Anemia&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Vachal,%20Petr&rft.date=2012-04-12&rft.volume=55&rft.issue=7&rft.spage=2945&rft.epage=2959&rft.pages=2945-2959&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm201542d&rft_dat=%3Cproquest_cross%3E1000405332%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=1000405332&rft_id=info:pmid/22364528&rfr_iscdi=true |