Structure-Based Design of Novel Class II c-Met Inhibitors: 2. SAR and Kinase Selectivity Profiles of the Pyrazolone Series

As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, <i>N</i>-(4-((6,7-dimethoxyquinolin-4-yl)­oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1<i>H</i>-pyrazole-4-carboxamide (<b>1</b>), was identified. Knowledge of the binding mode of this molecule in both c-Met and VEGFR-2 proteins led to a novel strategy for designing more selective analogues of <b>1</b>. Along with detailed SAR information, we demonstrate that the low kinase selectivity associated with class II c-Met inhibitors can be improved significantly. This work resulted in the discovery of potent c-Met inhibitors with improved selectivity profiles over VEGFR-2 and IGF-1R that could serve as useful tools to probe the relationship between kinase selectivity and in vivo efficacy in tumor xenograft models. Compound <b>59e</b> (AMG 458) was ultimately advanced into preclinical safety studies

Discovery of 1<i>H</i>‑Pyrazol-3(2<i>H</i>)‑ones as Potent and Selective Inhibitors of Protein Kinase R‑like Endoplasmic Reticulum Kinase (PERK)

The structure-based design and optimization of a novel series of selective PERK inhibitors are described resulting in the identification of <b>44</b> as a potent, highly selective, and orally active tool compound suitable for PERK pathway biology exploration both in vitro and in vivo