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Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase

2008; Elsevier BV; Volume: 18; Issue: 11 Linguagem: Inglês

10.1016/j.bmcl.2008.04.043

1464-3405

Derek A. Cogan, Ronald A. Aungst, Eric C. Breinlinger, Tazmeen N. Fadra, Daniel R. Goldberg, M Hao, Rachel Kroe‐Barrett, Neil Moss, Christopher Pargellis, Kevin Qian, Alan Swinamer,

Cancer Mechanisms and Therapy

A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.