Discovery of (R)‑8-(1-(3,5-Difluorophenylamino)ethyl)‑N,N‑dimethyl-2-morpholino-4-oxo‑4H‑chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers
Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamide...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-01, Vol.58 (2), p.943-962 |
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| container_title | Journal of medicinal chemistry |
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| creator | Barlaam, Bernard Cosulich, Sabina Degorce, Sébastien Fitzek, Martina Green, Stephen Hancox, Urs Lambert-van der Brempt, Christine Lohmann, Jean-Jacques Maudet, Mickaël Morgentin, Rémy Pasquet, Marie-Jeanne Péru, Aurélien Plé, Patrick Saleh, Twana Vautier, Michel Walker, Mike Ward, Lara Warin, Nicolas |
| description | Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials. |
| doi_str_mv | 10.1021/jm501629p |
| format | Article |
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We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm501629p</identifier><identifier>PMID: 25514658</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Aniline Compounds - chemical synthesis ; Aniline Compounds - pharmacology ; Animals ; Chromones - chemical synthesis ; Chromones - pharmacology ; Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors ; Dogs ; Drug Discovery ; Humans ; Male ; Mice ; Neoplasms, Experimental - chemistry ; Neoplasms, Experimental - drug therapy ; PTEN Phosphohydrolase - deficiency ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2015-01, Vol.58 (2), p.943-962</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm501629p$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm501629p$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25514658$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Barlaam, Bernard</creatorcontrib><creatorcontrib>Cosulich, Sabina</creatorcontrib><creatorcontrib>Degorce, Sébastien</creatorcontrib><creatorcontrib>Fitzek, Martina</creatorcontrib><creatorcontrib>Green, Stephen</creatorcontrib><creatorcontrib>Hancox, Urs</creatorcontrib><creatorcontrib>Lambert-van der Brempt, Christine</creatorcontrib><creatorcontrib>Lohmann, Jean-Jacques</creatorcontrib><creatorcontrib>Maudet, Mickaël</creatorcontrib><creatorcontrib>Morgentin, Rémy</creatorcontrib><creatorcontrib>Pasquet, Marie-Jeanne</creatorcontrib><creatorcontrib>Péru, Aurélien</creatorcontrib><creatorcontrib>Plé, Patrick</creatorcontrib><creatorcontrib>Saleh, Twana</creatorcontrib><creatorcontrib>Vautier, Michel</creatorcontrib><creatorcontrib>Walker, Mike</creatorcontrib><creatorcontrib>Ward, Lara</creatorcontrib><creatorcontrib>Warin, Nicolas</creatorcontrib><title>Discovery of (R)‑8-(1-(3,5-Difluorophenylamino)ethyl)‑N,N‑dimethyl-2-morpholino-4-oxo‑4H‑chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers</title><title>Journal of medicinal chemistry</title><addtitle>J. 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Cosulich, Sabina ; Degorce, Sébastien ; Fitzek, Martina ; Green, Stephen ; Hancox, Urs ; Lambert-van der Brempt, Christine ; Lohmann, Jean-Jacques ; Maudet, Mickaël ; Morgentin, Rémy ; Pasquet, Marie-Jeanne ; Péru, Aurélien ; Plé, Patrick ; Saleh, Twana ; Vautier, Michel ; Walker, Mike ; Ward, Lara ; Warin, Nicolas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a868-f917e56f1ea22a1d48f5511a0a1b3d209a374f816f3579adacc83917eb04c843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aniline Compounds - chemical synthesis</topic><topic>Aniline Compounds - pharmacology</topic><topic>Animals</topic><topic>Chromones - chemical synthesis</topic><topic>Chromones - pharmacology</topic><topic>Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors</topic><topic>Dogs</topic><topic>Drug Discovery</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Neoplasms, Experimental - chemistry</topic><topic>Neoplasms, Experimental - drug therapy</topic><topic>PTEN Phosphohydrolase - deficiency</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Barlaam, Bernard</creatorcontrib><creatorcontrib>Cosulich, Sabina</creatorcontrib><creatorcontrib>Degorce, Sébastien</creatorcontrib><creatorcontrib>Fitzek, Martina</creatorcontrib><creatorcontrib>Green, Stephen</creatorcontrib><creatorcontrib>Hancox, Urs</creatorcontrib><creatorcontrib>Lambert-van der Brempt, Christine</creatorcontrib><creatorcontrib>Lohmann, Jean-Jacques</creatorcontrib><creatorcontrib>Maudet, Mickaël</creatorcontrib><creatorcontrib>Morgentin, Rémy</creatorcontrib><creatorcontrib>Pasquet, Marie-Jeanne</creatorcontrib><creatorcontrib>Péru, Aurélien</creatorcontrib><creatorcontrib>Plé, Patrick</creatorcontrib><creatorcontrib>Saleh, Twana</creatorcontrib><creatorcontrib>Vautier, Michel</creatorcontrib><creatorcontrib>Walker, Mike</creatorcontrib><creatorcontrib>Ward, Lara</creatorcontrib><creatorcontrib>Warin, Nicolas</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Barlaam, Bernard</au><au>Cosulich, Sabina</au><au>Degorce, Sébastien</au><au>Fitzek, Martina</au><au>Green, Stephen</au><au>Hancox, Urs</au><au>Lambert-van der Brempt, Christine</au><au>Lohmann, Jean-Jacques</au><au>Maudet, Mickaël</au><au>Morgentin, Rémy</au><au>Pasquet, Marie-Jeanne</au><au>Péru, Aurélien</au><au>Plé, Patrick</au><au>Saleh, Twana</au><au>Vautier, Michel</au><au>Walker, Mike</au><au>Ward, Lara</au><au>Warin, Nicolas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of (R)‑8-(1-(3,5-Difluorophenylamino)ethyl)‑N,N‑dimethyl-2-morpholino-4-oxo‑4H‑chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2015-01-22</date><risdate>2015</risdate><volume>58</volume><issue>2</issue><spage>943</spage><epage>962</epage><pages>943-962</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Several studies have highlighted the dependency of PTEN deficient tumors to PI3Kβ activity and specific inhibition of PI3Kδ has been shown activity against human B-cell cancers. We describe the discovery and optimization of a series of 8-(1-anilino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxamides as PI3Kβ/δ inhibitors, which led to the discovery of the clinical candidate 13, also known as AZD8186. On the basis of the lower lipophilicity of the chromen-4-one core compared to the previously utilized pyrido[1,2-a]pyrimid-4-one core, this series of compounds displayed high metabolic stability and suitable physical properties for oral administration. Compound 13 showed profound pharmacodynamic modulation of p-Akt in PTEN-deficient PC3 prostate tumor bearing mice after oral administration and showed complete inhibition of tumor growth in the mouse PTEN-deficient PC3 prostate tumor xenograft model. 13 was selected as a clinical candidate for treatment of PTEN-deficient cancers and has recently entered phase I clinical trials.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25514658</pmid><doi>10.1021/jm501629p</doi><tpages>20</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2015-01, Vol.58 (2), p.943-962 |
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| source | ACS Publications; MEDLINE |
| subjects | Aniline Compounds - chemical synthesis Aniline Compounds - pharmacology Animals Chromones - chemical synthesis Chromones - pharmacology Class Ia Phosphatidylinositol 3-Kinase - antagonists & inhibitors Dogs Drug Discovery Humans Male Mice Neoplasms, Experimental - chemistry Neoplasms, Experimental - drug therapy PTEN Phosphohydrolase - deficiency Structure-Activity Relationship |
| title | Discovery of (R)‑8-(1-(3,5-Difluorophenylamino)ethyl)‑N,N‑dimethyl-2-morpholino-4-oxo‑4H‑chromene-6-carboxamide (AZD8186): A Potent and Selective Inhibitor of PI3Kβ and PI3Kδ for the Treatment of PTEN-Deficient Cancers |
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