A novel series of pyrazolones was recently identifi ed as potent inhibitors of c-Met. Increased selectivity over VEGFR-2 was achieved with the incorporation of a 2-hydroxypropyl group in the N1 position of the pyrazolone ring. Analysis of both in vitro and in vivo studies revealed oxidation of the hydroxyl group to form the corresponding ketone; an active metabolite lacking selectivity over VEGFR-2. Subsequent modifi cation of the 2-hydroxypropyl group led to the discovery of 1-(2-Hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458), a molecule that exhibits a favorable pharmacokinetic profi le in mouse, rat, dog, and monkey. Moreover, AMG 458 signifi cantly inhibited tumor growth when dosed orally in the TPR-Met and U-87 MG xenograft models with no adverse eff ect on body weight. As a result, AMG 458 was progressed as a potential clinical candidate for the treatment of human cancers.