Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors.

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.
Authors	Matthew C Lucas, Niala Bhagirath, Eric Chiao, David M Goldstein, Johannes C Hermann, Pei-Yuan Hsu, Stephan Kirchner, Joshua J Kennedy-Smith, Andreas Kuglstatter, Christine Lukacs, John Menke, Linghao Niu, Fernando Padilla, Ying Peng, Liudmila Polonchuk, Aruna Railkar, Michelle Slade, Michael Soth, Daigen Xu, Preeti Yadava, Calvin Yee, Mingyan Zhou, Cheng Liao
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 6 Pg. 2683-91 (Mar 27 2014) ISSN: 1520-4804 [Electronic] United States
PMID	24520947 (Publication Type: Journal Article)
Chemical References	Amides Ether-A-Go-Go Potassium Channels KCNH1 protein, human Protein Kinase Inhibitors Pyridazines Protein-Tyrosine Kinases
Topics	Amides (chemical synthesis, 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, pharmacokinetics, pharmacology) Protein-Tyrosine Kinases (antagonists & inhibitors) Pyridazines (chemical synthesis, pharmacokinetics, pharmacology) Rats Spleen (drug effects, enzymology) Structure-Activity Relationship X-Ray Diffraction

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