Potent HIV protease inhibitors containing a novel (hydroxyethyl)amide isostere.

Beaulieu PL, Wernic D, Abraham A, Anderson PC, Bogri T, Bousquet Y, Croteau G, Guse I, Lamarre D, Liard F, Paris W, Thibeault D, Pav S, Tong L.

Bio-Mega Research Division, Boehringer Ingelheim (Canada) Ltd., Laval (Quebec), Canada.

A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50 effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.

PMID: 9216835 [PubMed - indexed for MEDLINE]

Many of the current HIV-1 protease inhibitors have activity against HIV-2. I would suspect that this compound, does as well-- but it is a very long way from an X-ray structure to having a safe, effective and well tolerated drug. BY