Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position
[Display omitted] We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modificati...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2016-06, Vol.26 (11), p.2724-2729 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 26 |
| creator | Jordan, Allan M. Begum, Habiba Fairweather, Emma Fritzl, Samantha Goldberg, Kristin Hopkins, Gemma V. Hamilton, Niall M. Lyons, Amanda J. March, H. Nikki Newton, Rebecca Small, Helen F. Vishwanath, Swamy Waddell, Ian D. Waszkowycz, Bohdan Watson, Amanda J. Ogilvie, Donald J. |
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We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging. |
| doi_str_mv | 10.1016/j.bmcl.2016.03.100 |
| format | Article |
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We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2016.03.100</identifier><identifier>PMID: 27086121</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Aniline Compounds - chemical synthesis ; Aniline Compounds - chemistry ; Aniline Compounds - pharmacology ; Dose-Response Relationship, Drug ; Hepatocyte stability ; Humans ; Kinase inhibitor ; Lung cancer ; Models, Molecular ; Molecular Structure ; Protein Kinase Inhibitors - chemical synthesis ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins c-ret - antagonists & inhibitors ; Proto-Oncogene Proteins c-ret - metabolism ; Quinazolines - chemical synthesis ; Quinazolines - chemistry ; Quinazolines - pharmacology ; RET receptor ; Structure-Activity Relationship ; Targeted therapy</subject><ispartof>Bioorganic & medicinal chemistry letters, 2016-06, Vol.26 (11), p.2724-2729</ispartof><rights>2016 Elsevier Ltd</rights><rights>Copyright © 2016 Elsevier Ltd. All rights reserved.</rights><rights>2016 The Authors. Published by Elsevier Ltd. 2016 Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-f1ea2a0c96b6ebeca131c1aa1e9e41e5ed5d689c4f8da1075bcb1751af21eec83</citedby><cites>FETCH-LOGICAL-c488t-f1ea2a0c96b6ebeca131c1aa1e9e41e5ed5d689c4f8da1075bcb1751af21eec83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2016.03.100$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27086121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jordan, Allan M.</creatorcontrib><creatorcontrib>Begum, Habiba</creatorcontrib><creatorcontrib>Fairweather, Emma</creatorcontrib><creatorcontrib>Fritzl, Samantha</creatorcontrib><creatorcontrib>Goldberg, Kristin</creatorcontrib><creatorcontrib>Hopkins, Gemma V.</creatorcontrib><creatorcontrib>Hamilton, Niall M.</creatorcontrib><creatorcontrib>Lyons, Amanda J.</creatorcontrib><creatorcontrib>March, H. Nikki</creatorcontrib><creatorcontrib>Newton, Rebecca</creatorcontrib><creatorcontrib>Small, Helen F.</creatorcontrib><creatorcontrib>Vishwanath, Swamy</creatorcontrib><creatorcontrib>Waddell, Ian D.</creatorcontrib><creatorcontrib>Waszkowycz, Bohdan</creatorcontrib><creatorcontrib>Watson, Amanda J.</creatorcontrib><creatorcontrib>Ogilvie, Donald J.</creatorcontrib><title>Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.</description><subject>Aniline Compounds - chemical synthesis</subject><subject>Aniline Compounds - chemistry</subject><subject>Aniline Compounds - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Hepatocyte stability</subject><subject>Humans</subject><subject>Kinase inhibitor</subject><subject>Lung cancer</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Protein Kinase Inhibitors - chemical synthesis</subject><subject>Protein Kinase Inhibitors - chemistry</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins c-ret - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-ret - metabolism</subject><subject>Quinazolines - chemical synthesis</subject><subject>Quinazolines - chemistry</subject><subject>Quinazolines - pharmacology</subject><subject>RET receptor</subject><subject>Structure-Activity Relationship</subject><subject>Targeted therapy</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFO3DAURa0KVKa0P9AFypJNpn6JkzhShYTQlCIhISFadWc5zgvzpok92BmksupH8IV8CY4GEGxY-en6-D7rXsa-Ap8Dh_Lbat4Mpp9ncZ7zPGr8A5uBKEWaC17ssBmvS57KWvzZY59CWHEOggvxke1lFZclZDBjv48t9WTdzYasvnNxxITskhoanQ-J65Jxicnl4ir5G4GASesGTfbh__2i143zeiRnn7EqXbtAk_KZ7Xa6D_jl6dxnv34srk5-pucXp2cnx-epEVKOaQeoM81NXTYlNmg05GBAa8AaBWCBbdGWsjaik60GXhWNaaAqQHcZIBqZ77Ojre960wzYGrSj171aexq0_6ecJvX2xtJSXbtbJWRd1jmPBodPBj5mgGFUAwWDfa8tuk1QIGNSVSZyiGi2RY13IXjsXtYAV1MhaqWmQtRUiOJ51Cb_g9cffHny3EAEvm8BjDHdEnoVDKE12JJHM6rW0Xv-j9KDoHg</recordid><startdate>20160601</startdate><enddate>20160601</enddate><creator>Jordan, Allan M.</creator><creator>Begum, Habiba</creator><creator>Fairweather, Emma</creator><creator>Fritzl, Samantha</creator><creator>Goldberg, Kristin</creator><creator>Hopkins, Gemma V.</creator><creator>Hamilton, Niall M.</creator><creator>Lyons, Amanda J.</creator><creator>March, H. Nikki</creator><creator>Newton, Rebecca</creator><creator>Small, Helen F.</creator><creator>Vishwanath, Swamy</creator><creator>Waddell, Ian D.</creator><creator>Waszkowycz, Bohdan</creator><creator>Watson, Amanda J.</creator><creator>Ogilvie, Donald J.</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</general><scope>6I.</scope><scope>AAFTH</scope><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>5PM</scope></search><sort><creationdate>20160601</creationdate><title>Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position</title><author>Jordan, Allan M. ; Begum, Habiba ; Fairweather, Emma ; Fritzl, Samantha ; Goldberg, Kristin ; Hopkins, Gemma V. ; Hamilton, Niall M. ; Lyons, Amanda J. ; March, H. Nikki ; Newton, Rebecca ; Small, Helen F. ; Vishwanath, Swamy ; Waddell, Ian D. ; Waszkowycz, Bohdan ; Watson, Amanda J. ; Ogilvie, Donald J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c488t-f1ea2a0c96b6ebeca131c1aa1e9e41e5ed5d689c4f8da1075bcb1751af21eec83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aniline Compounds - chemical synthesis</topic><topic>Aniline Compounds - chemistry</topic><topic>Aniline Compounds - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Hepatocyte stability</topic><topic>Humans</topic><topic>Kinase inhibitor</topic><topic>Lung cancer</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - chemistry</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins c-ret - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-ret - metabolism</topic><topic>Quinazolines - chemical synthesis</topic><topic>Quinazolines - chemistry</topic><topic>Quinazolines - pharmacology</topic><topic>RET receptor</topic><topic>Structure-Activity Relationship</topic><topic>Targeted therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jordan, Allan M.</creatorcontrib><creatorcontrib>Begum, Habiba</creatorcontrib><creatorcontrib>Fairweather, Emma</creatorcontrib><creatorcontrib>Fritzl, Samantha</creatorcontrib><creatorcontrib>Goldberg, Kristin</creatorcontrib><creatorcontrib>Hopkins, Gemma V.</creatorcontrib><creatorcontrib>Hamilton, Niall M.</creatorcontrib><creatorcontrib>Lyons, Amanda J.</creatorcontrib><creatorcontrib>March, H. Nikki</creatorcontrib><creatorcontrib>Newton, Rebecca</creatorcontrib><creatorcontrib>Small, Helen F.</creatorcontrib><creatorcontrib>Vishwanath, Swamy</creatorcontrib><creatorcontrib>Waddell, Ian D.</creatorcontrib><creatorcontrib>Waszkowycz, Bohdan</creatorcontrib><creatorcontrib>Watson, Amanda J.</creatorcontrib><creatorcontrib>Ogilvie, Donald J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jordan, Allan M.</au><au>Begum, Habiba</au><au>Fairweather, Emma</au><au>Fritzl, Samantha</au><au>Goldberg, Kristin</au><au>Hopkins, Gemma V.</au><au>Hamilton, Niall M.</au><au>Lyons, Amanda J.</au><au>March, H. Nikki</au><au>Newton, Rebecca</au><au>Small, Helen F.</au><au>Vishwanath, Swamy</au><au>Waddell, Ian D.</au><au>Waszkowycz, Bohdan</au><au>Watson, Amanda J.</au><au>Ogilvie, Donald J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2016-06-01</date><risdate>2016</risdate><volume>26</volume><issue>11</issue><spage>2724</spage><epage>2729</epage><pages>2724-2729</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
We have previously reported a series of anilinoquinazoline derivatives as potent and selective biochemical inhibitors of the RET kinase domain. However, these derivatives displayed diminished cellular potency. Herein we describe further optimisation of the series through modification of their physicochemical properties, delivering improvements in cell potency. However, whilst cellular selectivity against key targets could be maintained, combining cell potency and acceptable pharmacokinetics proved challenging.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27086121</pmid><doi>10.1016/j.bmcl.2016.03.100</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Aniline Compounds - chemical synthesis Aniline Compounds - chemistry Aniline Compounds - pharmacology Dose-Response Relationship, Drug Hepatocyte stability Humans Kinase inhibitor Lung cancer Models, Molecular Molecular Structure Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-ret - antagonists & inhibitors Proto-Oncogene Proteins c-ret - metabolism Quinazolines - chemical synthesis Quinazolines - chemistry Quinazolines - pharmacology RET receptor Structure-Activity Relationship Targeted therapy |
| title | Anilinoquinazoline inhibitors of the RET kinase domain—Elaboration of the 7-position |
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