Pseudo-symmetrical difluoroketones. Highly potent and specific inhibitors of HIV-1 protease.

A series of novel, pseudo-symmetrical difluoroketones which are highly potent inhibitors of the HIV-1 protease (IC50 = 1.55-0.02 nM) were synthesized. These compounds also possess good antiviral activity by inhibition of the cytopathic effect of HIV-13B in MT-4 cells in vitro.

Kinetic characterization, stereoselectivity, and species selectivity of the inhibition of plant acetyl-CoA carboxylase by the aryloxyphenoxypropionic acid grass herbicides.

The selective grass herbicides diclofop, haloxyfop, and trifop were found to be potent reversible inhibitors of acetyl-CoA carboxylase from the susceptible species barley, corn, and wheat. Kis values with variable concentrations of acetyl-CoA ranged from 0.01 to 0.06 microM at pH 8.5 depending on the species of grass. Inhibition of the wheat enzyme by diclofop was noncompetitive versus acetyl-CoA with Kis less than Kii and noncompetitive versus MgATP and bicarbonate, but with Kis approximately equal to Kii. Since the apparent inhibition constant was most sensitive to the level of acetyl-CoA, these compounds probably interact with the transcarboxylase site rather than the biotin carboxylation site. With the wheat enzyme the Kis value for the R-(+)-enantiomer of trifop was 1.98 +/- 0.22 times lower than that of the racemic mixture. This confirms the stereoselectivity observed in the whole plant. The enzyme from tolerant broadleaf species (spinach and mung bean) was much less sensitive to these herbicides (Kis values varied from 16 to 515 microM). These data confirm that acetyl-CoA carboxylase is the site of action for the aryloxyphenoxypropionic acid herbicides and may explain their selectivity for monocotyledenous species.

Design of orally bioavailable, symmetry-based inhibitors of HIV protease.

A series of novel inhibitors of HIV-1 protease with excellent oral bioavailability is described. Differential acylation of the two amino groups of symmetry-based diamine core groups 2-5 led to unsymmetrically substituted inhibitors 17-43, many of which inhibited HIV protease at subnanomolar concentrations. Anti-HIV activity in vitro was observed at 0.1-1 microM. A systematic evaluation of the pharmacokinetic behavior of these inhibitors in rats identified the influence of aqueous solubility, molecular size and hydrogen-bonding functionality. Compound 30 (A-80987) was selected for further evaluation based on a favorable Cmax/ ED50 ratio (> 20) and half-life (> 2 h).