Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.

摘要: Optimization of a series 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 was obviated by replacement moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide solvent front heterocycle. Consideration ground state bound energetics allowed rapid realization improved substituents affording subnanomolar Syk potency high selectivity. These molecules were also devoid mutagenicity risk as assessed via test using TA97a Salmonella strain.