Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors [electronic resource] : Leveraging Ground State Interactions To Accelerate Optimization

• Ngôn ngữ: eng
• Ký hiệu phân loại: 547.2 Organic chemical reactions formerly 547.139
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2016
• Mô tả vật lý: Size: p. 1151-1155 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260792
• Chủ đề: 1. 37 inorganic, organic, physical, and analytical chemistry; 2. 60 applied life sciences; 3. Conformation; 4. Indoles; 5. Inhibitors; 6. Intramolecular hydrogen bond; 7. Peptides and proteins; 8. Rodent models; 9. Spleen tyrosine kinase; 10. Structure-based drug design

Tóm tắt

Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.