SELECTIVITY IN THE INHIBITION OF HIV AND FIV PROTEASE - INHIBITORY AND MECHANISTIC STUDIES OF PYRROLIDINE-CONTAINING ALPHA-KETO AMIDE AND HYDROXYETHYLAMINE CORE STRUCTURES

This paper describes the development of new pyrrolidine-containing alp ha-keto amide and hydroxyethylamine core structures as mechanism based inhibitors of the HIV and FIV proteases. It was found that the alpha- keto amide core structure 2 is approximately 300-fold better than the corresponding hydroxyethylamine isosteric structure and 1300-fold bett er than the corresponding phosphinic acid derivative as an inhibitor o f the HIV protease. The alpha-keto amide is however not hydrated until it is bound to the HIV protease as indicated by the NMR study and the X-ray structural analysis. Further analysis of the inhibition activit ies of hydroxyethylamine isosteres containing modified pyrrolidine der ivatives revealed that a cis-methoxy group at C-4 of the pyrrolidine w ould improve the binding 5-and 25-fold for the trans-isomer. When this strategy was applied to the alpha-keto amide isostere, a cis-benzyl e ther at C-4 was found to enhance binding 3-fold. Of the core structure s prepared as inhibitors of the HIV protease, none show significant in hibitory activity against the mechanistically identical FIV protease, and additional complementary groups are needed to improve inhibition.