The benzyl alcohol was the first group identified as conferring a metabolic liability and N-dealkylation of the N-methylaminopyrimidine was also anticipated to be a likely metabolic pathway. Isosteric replacements for the benzyl alcohol were introduced and the desmethyl aminopyrimidine analogues were prepared whilst ensuring that logP and MW were not increased significantly. 2-Methoxypyridines were identified as the preferred benzyl alcohol replacements and, in combination with the desmethyl amino modification, were found to lower clearance and improve mTOR potency (the N-Me substituent was postulated to make an unfavourable interaction with the mTOR protein). The cyclopentyl group in 2 was then modified to optimise potency and improve solubility through the addition of polar substituents. Hydroxyethyl-substituted cyclohexanol in this position gave the optimal balance of properties and led to the identification of their clinical candidate, PF-04691502 (Ki= and 16 nM at PI3Kα and mTOR respectively), which was subsequently advanced into a phase I clinical trial . The progression from 2 to PF-04691502 nicely illustrates the use of structure-based design to optimise multiple physicochemical properties and the authors illustrate this succinctly (see below) using a plot of the mPI3Kα potency vs cLogP overlaid with contours of equivalent lipophilic efficiency ( LipE ). In moving from compound 2 to the eventual candidate 1 (PF-04691502) the LipE was increased from under 6 to about 8. The x-ray co-crystal structure ( PDB3ML9 ) of PF-04691502 revealed a number of interesting features (see above), including a water-mediated H-bond and an internal H-bond.