MEDI 233 |
| The discovery of potent and selective c-Met (HGFR) 2-aminopyridine-4-phenyl inhibitors is presented. Optimization of the kinase inhibitory potency (Ki=210 nM) and the cell potency of the initial lead (IC50=1 microM) is described. This optimization effort involved synthesizing 30 compounds and led to the discovery of a lead compound with improved potency (Ki=20 nM; IC50=40 nM), metabolic stability (t1/2=260 min) and physical properties (solubility>200 microM) relative to the initial lead. The development of a chiral synthetic route to this improved molecule utilizing biotransformation is also described along with PK/PD and TGI experiments.
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General Oral Session
1:30 PM-4:50 PM, Tuesday, August 21, 2007 BCEC -- 210A, Oral
Division of Medicinal Chemistry |
