Dihydroxy-pyrimidine and N-methylpyrimidone HIV-integrase inhibitors: Improving cell based activity by the quaternarization of a chiral center

In the context of HIV-integrase, dihydroxypyrimidine and N-methyl pyrimidone inhibitors the cellular activity of this class of compounds has been optimized by the introduction of a simple methyl substituent in the α-position of the C-2 side chains. Enhanced passive membrane permeability has been identified as the key factor driving the observed cell-based activity improvement. The rat PK profile of the α-methyl derivative 26a was also improved over its des-methyl exact analog.