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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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-03, Vol.57 (6), p.2683-2691
Main Authors: 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
Format: Article
Language:English
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
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401982j