This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.

LB-147 Over expression and amplification of Aurora-2, a key regulator of mitosis plays important but distinct roles in the G2 and M phases of the cell cycle and has been reported in different tumor types including breast, colon, pancreatic, ovarian and gastric cancer. We report herein the discovery and preclinical profile of PF-3814735, a novel heretofore unreported pyrimidine scaffold based ATP-competitive, reversible inhibitor of Aurora-1 and 2 kinases. SAR at the C2 and C4 positions of the pyrimidine scaffold led to a series with great in vitro potency. Subsets of analogs from this series that demonstratedexcellent in vitro ADME profile were selected for further in vivo pharmacological and ADME profiling. These efforts led to the discovery of PF-3814735, which inhibits Aurora-1 kinase with an IC50 value of 0.8 nM and Aurora-2 kinase with an IC50 value of 5 nM and has corresponding potent cellular and biochemical activity. Oral administration of PF-3814735 demonstrated in vivo pharmacology and high oral bioavailability (%F>50). Treatment with PF-3814735 resulted in significant tumor growth inhibition at tolerable doses in multiple tumor xenograft models. In summary, we will be describing the chemistry and SAR that led to the discovery of a potent Aurora kinase inhibitor, PF-3814735 that is the clinical candidate and is currently in Phase I trials. Design,synthesis, inhibitor kinase and cell activity, kinase selectivityprofile, ADME as well as inhibitor chemical structure will be presented.