Using Ovality to Predict Nonmutagenic, Orally Efficacious Pyridazine Amides as Cell Specific Spleen Tyrosine Kinase Inhibitors

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 27, 2014
• 年：2014
• 卷：57
• 期：6
• 页码：2683-2691
• 全文大小：441K
• 年卷期：v.57,no.6(March 27, 2014)
• ISSN：1520-4804

文摘

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.