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Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors
Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibito...
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| Published in: | Journal of medicinal chemistry 2014-03, Vol.57 (6), p.2683-2691 |
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-a315t-dbd70c9b87299598ef60b64492043ca5f7549689c25fdf485f6b55c2e774744a3 |
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| cites | cdi_FETCH-LOGICAL-a315t-dbd70c9b87299598ef60b64492043ca5f7549689c25fdf485f6b55c2e774744a3 |
| container_end_page | 2691 |
| container_issue | 6 |
| container_start_page | 2683 |
| container_title | Journal of medicinal chemistry |
| container_volume | 57 |
| creator | Lucas, Matthew C Bhagirath, Niala Chiao, Eric Goldstein, David M Hermann, Johannes C Hsu, Pei-Yuan Kirchner, Stephan Kennedy-Smith, Joshua J Kuglstatter, Andreas Lukacs, Christine Menke, John Niu, Linghao Padilla, Fernando Peng, Ying Polonchuk, Liudmila Railkar, Aruna Slade, Michelle Soth, Michael Xu, Daigen Yadava, Preeti Yee, Calvin Zhou, Mingyan Liao, Cheng |
| description | Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented. |
| doi_str_mv | 10.1021/jm401982j |
| format | article |
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We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. 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Med. Chem</addtitle><description>Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. 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Bhagirath, Niala ; Chiao, Eric ; Goldstein, David M ; Hermann, Johannes C ; Hsu, Pei-Yuan ; Kirchner, Stephan ; Kennedy-Smith, Joshua J ; Kuglstatter, Andreas ; Lukacs, Christine ; Menke, John ; Niu, Linghao ; Padilla, Fernando ; Peng, Ying ; Polonchuk, Liudmila ; Railkar, Aruna ; Slade, Michelle ; Soth, Michael ; Xu, Daigen ; Yadava, Preeti ; Yee, Calvin ; Zhou, Mingyan ; Liao, Cheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-dbd70c9b87299598ef60b64492043ca5f7549689c25fdf485f6b55c2e774744a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amides - chemical synthesis</topic><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>Computational Biology</topic><topic>Computer Simulation</topic><topic>Drug Design</topic><topic>Ether-A-Go-Go Potassium Channels - drug effects</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Mutagenesis - drug effects</topic><topic>Mutagenicity Tests</topic><topic>Protein Kinase Inhibitors - chemical synthesis</topic><topic>Protein Kinase Inhibitors - pharmacokinetics</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Pyridazines - chemical synthesis</topic><topic>Pyridazines - pharmacokinetics</topic><topic>Pyridazines - pharmacology</topic><topic>Rats</topic><topic>Spleen - drug effects</topic><topic>Spleen - enzymology</topic><topic>Structure-Activity Relationship</topic><topic>X-Ray Diffraction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lucas, Matthew C</creatorcontrib><creatorcontrib>Bhagirath, Niala</creatorcontrib><creatorcontrib>Chiao, Eric</creatorcontrib><creatorcontrib>Goldstein, David M</creatorcontrib><creatorcontrib>Hermann, Johannes C</creatorcontrib><creatorcontrib>Hsu, Pei-Yuan</creatorcontrib><creatorcontrib>Kirchner, Stephan</creatorcontrib><creatorcontrib>Kennedy-Smith, Joshua J</creatorcontrib><creatorcontrib>Kuglstatter, Andreas</creatorcontrib><creatorcontrib>Lukacs, Christine</creatorcontrib><creatorcontrib>Menke, John</creatorcontrib><creatorcontrib>Niu, Linghao</creatorcontrib><creatorcontrib>Padilla, Fernando</creatorcontrib><creatorcontrib>Peng, Ying</creatorcontrib><creatorcontrib>Polonchuk, Liudmila</creatorcontrib><creatorcontrib>Railkar, Aruna</creatorcontrib><creatorcontrib>Slade, Michelle</creatorcontrib><creatorcontrib>Soth, Michael</creatorcontrib><creatorcontrib>Xu, Daigen</creatorcontrib><creatorcontrib>Yadava, Preeti</creatorcontrib><creatorcontrib>Yee, Calvin</creatorcontrib><creatorcontrib>Zhou, Mingyan</creatorcontrib><creatorcontrib>Liao, Cheng</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>Lucas, Matthew C</au><au>Bhagirath, Niala</au><au>Chiao, Eric</au><au>Goldstein, David M</au><au>Hermann, Johannes C</au><au>Hsu, Pei-Yuan</au><au>Kirchner, Stephan</au><au>Kennedy-Smith, Joshua J</au><au>Kuglstatter, Andreas</au><au>Lukacs, Christine</au><au>Menke, John</au><au>Niu, Linghao</au><au>Padilla, Fernando</au><au>Peng, Ying</au><au>Polonchuk, Liudmila</au><au>Railkar, Aruna</au><au>Slade, Michelle</au><au>Soth, Michael</au><au>Xu, Daigen</au><au>Yadava, Preeti</au><au>Yee, Calvin</au><au>Zhou, Mingyan</au><au>Liao, Cheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-03-27</date><risdate>2014</risdate><volume>57</volume><issue>6</issue><spage>2683</spage><epage>2691</epage><pages>2683-2691</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Inhibition of spleen tyrosine kinase has attracted much attention as a mechanism for the treatment of cancers and autoimmune diseases such as asthma, rheumatoid arthritis, and systemic lupus erythematous. We report the structure-guided optimization of pyridazine amide spleen tyrosine kinase inhibitors. Early representatives of this scaffold were highly potent and selective but mutagenic in an Ames assay. An approach that led to the successful identification of nonmutagenic examples, as well as further optimization to compounds with reduced cardiovascular liabilities is described. Select pharmacokinetic and in vivo efficacy data are presented.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24520947</pmid><doi>10.1021/jm401982j</doi><tpages>9</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2014-03, Vol.57 (6), p.2683-2691 |
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| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm401982j |
| source | American Chemical Society:Jisc Collections:American Chemical Society Read & Publish Agreement 2022-2024 (Reading list) |
| subjects | Amides - chemical synthesis Amides - pharmacology Animals Computational Biology Computer Simulation Drug Design Ether-A-Go-Go Potassium Channels - drug effects Humans In Vitro Techniques Mice Microsomes, Liver - metabolism Models, Molecular Molecular Conformation Mutagenesis - drug effects Mutagenicity Tests Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Protein-Tyrosine Kinases - antagonists & inhibitors Pyridazines - chemical synthesis Pyridazines - pharmacokinetics Pyridazines - pharmacology Rats Spleen - drug effects Spleen - enzymology Structure-Activity Relationship X-Ray Diffraction |
| title | Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors |
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