HIV-PR inhibitors currently used as anti AIDS drugs

Aspartic proteases have thus become important therapeutic targets and peptidomimetic inhibitors of these enzymes show great promise in the treatment of hypertension, AIDS and other diseases. In the field of organic chemistry, this has fostered an array of studies directed at the development of novel, stereoselective strategies for the synthesis of compounds containing multiple stereocenters, in enantiomerically pure form, to be used in the development of new reversible inhibitors.

Several low molecular weight inhibitors of HIV-1 protease (MW<1000 Da) are now used in humans, including saquinavir, riton­avir, indinavir, nelfinavir, and amprenavir

Ro-318959
Saquinavir
IC50 = 0.4 nM

ABT-538
Ritonavir
Ki = 0.02 nM

AG1343
Nelfinavir
Ki = 2.0 nM

MK-639
Indinavir
Ki = 0.34 nM

VX-478
Amprenavir
Ki = 0.60 nM

These are among the first successful examples of receptor/structure-based designed drugs and were de­veloped from structural studies of inhibitors bound in the active site of HIV-1 protease combined with the knowledge on inhibitors of other aspartic proteases (e.g. renin).36,[i] Notably, all these molecules exhibit common characteristics: a hydroxy-containing isostere and hydrophobic residues at P1/P1’, tipically Phe-mimicking benzyl groups.


[i] a) RobertsN.A., Martin, J.A., Kinchington, D., Broadhurst, A.V., Craig, J.C., Duncan, I.B., Galpin, S.A., Handa, B.K., Kay, J., Kröhn, A., Lambert,  R.W., Merrett, J.H., Mills, J.S., Parkes, K.E.B., Redshaw, S., Ritchie, A.J., Taylor, D.L., Thomas, G.J. & Machin, P.J. Science 1990, 248, 358-361; b) DorseyB.D., Levin, R.B., McDaniel, S.L., Vacca, J.P., Guare, J.P., Darke, P.L., Zugay, J.A., Emini, E.A., Schleif, W.A., Quintero, J.C., Lin, J.H.,  Chen, I-W., Holloway, M.K., Fitzgerald, P.M.D., Axel, M.G., Ostovic, D., Anderson, P.S. & Huff, J.R. J. Med. Chem. 1994, 37, 3443-3451; c) Varney, M.D., Appelt, K., Kalish, V., Reddy, M.R., Tatlock, J., Palmer, C.L., Romines, W.H., Wu, B.W. & Musick, L. J. Med. Chem. 1994, 37, 2274-2284; d) Kempf, D. J.; Marsh, K. C.; Denissen, J. F.; McDonald, E.; Vasavanonda, S.; Flentge, C.A.; Green, B. E.; Fino, L.; Park, C. H.; Kong, X. P.; Wideburg,  N. E.; Saldivar, A.; Ruiz, L.; Kati, W. M.; Sham, H. L.; Robins, T.; Stewart, K. T.; Hsu, A.; Plattner, J. J.; Leonard, J. M.; Norbeck, D. W. Proc. Natl. Acad. Sci. USA 1995, 92, 2484-2488.