We describe 3D-QSAR assisted design of an Aurora A inhibitor 67  with improved physico-chemical properties, in vitro activity, and in vivo PK profiles than the initial lead 24  . Three different 3D-QSAR models were built and validated using a set of 66 pyrazole (Model I) and furanopyrimidine (Model II) compounds with Aurora kinase A IC50 ranging from 33 nM to 10.5 mM. The best Model III, constructed using 24 training set ompounds from both series, showed robustness (r2CV = 0.54 and 0.52, for CoMFA and CoMSIA) as well as superior redictive abilities for forty two test set compounds (R2pred= 0.52 and 0.67, for CoMFA and CoMSIA). Superimposition of CoMFA and CoMSIA Model III over the crystal structure of Aurora A, suggests the possibility to improve the activity of the ligands by decreasing the steric clash with Val147 and Leu139 and by increasing the hydrophobic contact with Leu139 and Gly216 residues in the solvent exposed region of the enzyme. Based on these suggestions, rational redesign of furanopyrimidine 24  (cLogP = 7.41; Aurora A, IC50 = 43 nM; HCT-116, IC50 = 400 nM) led to the identification of quinazoline 67  (cLogP = 5.28; Aurora A, IC50 = 25 nM; HCT-116, IC50 = 23 nM). Rat in vivo pharmacokinetic study showed that 67  has better systemic exposure after iv administration than 24 , and has potential for further development.

3D-QSAR assisted drug design: Identification of a potent quinazoline based Aurora kinase inhibitor

245th National Meeting (2013)

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