848472-36-6Relevant articles and documents
Overcoming mutagenicity and ion channel activity: Optimization of selective spleen tyrosine kinase inhibitors
Ellis, J. Michael,Altman, Michael D.,Bass, Alan,Butcher, John W.,Byford, Alan J.,Donofrio, Anthony,Galloway, Sheila,Haidle, Andrew M.,Jewell, James,Kelly, Nancy,Leccese, Erica K.,Lee, Sandra,Maddess, Matthew,Miller, J. Richard,Moy, Lily Y.,Osimboni, Ekundayo,Otte, Ryan D.,Reddy, M. Vijay,Spencer, Kerrie,Sun, Binyuan,Vincent, Stella H.,Ward, Gwendolyn J.,Woo, Grace H. C.,Yang, Chiming,Houshyar, Hani,Northrup, Alan B.
supporting information, p. 1929 - 1939 (2015/04/27)
Development of a series of highly kinome-selective spleen tyrosine kinase (Syk) inhibitors with favorable druglike properties is described. Early leads were discovered through X-ray crystallographic analysis, and a systematic survey of cores within a selected chemical space focused on ligand binding efficiency. Attenuation of hERG ion channel activity inherent within the initial chemotype was guided through modulation of physicochemical properties including log D, PSA, and pKa. PSA proved most effective for prospective compound design. Further profiling of an advanced compound revealed bacterial mutagenicity in the Ames test using TA97a Salmonella strain, and subsequent study demonstrated that this mutagenicity was pervasive throughout the series. Identification of intercalation as a likely mechanism for the mutagenicity-enabled modification of the core scaffold. Implementation of a DNA binding assay as a prescreen and models in DNA allowed resolution of the mutagenicity risk, affording molecules with favorable potency, selectivity, pharmacokinetic, and off-target profiles.
Exploration of the active site of neuronal nitric oxide synthase by the design and synthesis of pyrrolidinomethyl 2-aminopyridine derivatives
Ji, Haitao,Delker, Silvia L.,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
scheme or table, p. 7804 - 7824 (2011/02/25)
Neuronal nitric oxide synthase (nNOS) represents an important therapeutic target for the prevention of brain injury and the treatment of various neurodegenerative disorders. A series of trans-substituted amino pyrrolidinomethyl 2-aminopyridine derivatives
NOS INHIBITORS FOR TREATMENT OF MOTOR DEFICIT DISORDERS
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Page/Page column 4; 5/8, (2008/06/13)
The present invention relates to preventive therapies and treatments of motor deficit disorders. In particular, the present invention relates to compositions and methods for preventative therapy and treatment of motor deficit disorders, such as cerebral p