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A series of novel, pseudo-symmetrical diduoroketones which are highly potent inhibitors of the RN-1 protease (IC,, = 1.55-0.02 nM) were synthesized. These compounds also possess good antiviral activity by inhibition of the cytopathic effect of HIV-l,, in MI"*4 cells in vitro.WIV-1; Protease inhibitor; Difluoroketone; Anti-viral The human immunodeficiency virus (HIV), which is the causative agent of AIDS, encodes a protease which proteolytically processes the gag and gag-pol polyproteins to form the mature proteins needed for the production of infectious viral particles [l]* The HIV-l protease is a member of the aspartic acid protease family and has been shown by X-ray ~~stallo~aph~ to be a C-2 symmetrical dimer [2,3]. Replacement of the aspartic acid residues at the eatalytiic active site by site-directed mutagenesis leads to the formation of immature, noninfective virions [4,53. For this reason, the HIV protease is considered as an important target for the development of agents for the treatment of HIV infection. Towards this end, potent and selective inhibitors of HIV protease have been shown to inhibit the spread of HIV infection in vitro [6-141.We wish to report the synthesis and the biological evaluation of a novel series of pseudo-symmetrical difluoroketones which complements the symmetric, dimeric nature of the HIV-l protease. This series, which is represented by the generic structure 1 in Scheme 1, displays highly potent and selective activity against the HIV protease. The activities of these compounds against a series of other aspartic acid proteases such as renin, pepsin or cathepsin D are at least 5 to 6 orders of magnitude less potent. 144HIV protease is replaced by a non-hydroly~ble difluoroketone transition state mimic [ 151 in these inhibitors. The P, and Pi side chains are kept identical (benzyl or isobutyl). The N-terminal blocking group represented by T (see Scheme 1) can be benzyloxycarbonyl, 2-pyridyl-carbamate, 2-pyridyl-urea or 2-pyridyl-sulfonamide to provide a range of different aqueous solubilities to the inhibitors [16]. MATERIALS AND METHUDSThe synthesis of the novel series of~~uoroketon~ represented by the generic structure I is outlined in Scheme 1. The addition of benay or isobutyl magnesium chloride to the known amide 2 [17] by the procedure of Weinreb [18] provided intermediate ketone 3. Oxime formation and catalytic hydrogenation provided the corresponding amine 4 (as a mixture of S and R configuration) which can be chromatographically separated and the S-amine was used for further reaction. The assignment of the stereochemistry was based on X-ray crystallography [17j. Opening of the oxazolidinone ring in 4 by basic hydrolysis and coupling with the protected L-valine fragment using DCC/HOBt coupling conditions provided compound 5. Oxidation of 5 with sodium dichromate in acetic acid 119] provided the series of diAuoroketones f.HIV-1 protease inhibition was measured by a fluorescence assay [20] using recombinant HIV-l protease, isolated as described previously [21]+ Reactions ...