HIV PIs Research Articles

2-Pyridyl P1′-Substituted Symmetry-Based Human Immunodeficiency Virus Protease Inhibitors (A-792611 and A-790742) with Potential for Convenient Dosing and Reduced Side Effects

A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.

Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors

Background Although recommended as initial therapy for patients with dyslipidemia who are taking human immunodeficiency virus protease inhibitors (HIV PIs), the effects of pravastatin on lipoproteins and arterial reactivity have not been elucidated. The purpose of this study was to determine the effects of pravastatin on lipoprotein subfractions and endothelial function in patients with dyslipidemia who are receiving HIV PIs. Methods This was a placebo-controlled, double-blind, crossover study comparing pravastatin (40 mg) to placebo in 20 patients who were taking HIV PIs. Lipoprotein subfractions were measured with nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was evaluated with high-resolution ultrasound scanning. Results At baseline, subjects had an increased concentration of low-density lipoprotein (LDL) particles (1756 ± 180 nmol/L), which tended to be small (19.9 ± 0.2 nm), a low concentration of large high-density lipoproteins (HDL; 0.94 ± 0.07 mmol/L), and an increased concentration of large very low-density lipoproteins (VLDL; 1.90 ± 0.58 mmol/L). FMD was impaired (4.5% ± 1.1%). Compared with placebo, pravastatin resulted in a 20.8% reduction in LDL particles ( P = .030), a 26.7% reduction in small LDL ( P = .100), and a 44.9% reduction in small VLDL ( P = .023). Total and non-HDL cholesterol levels decreased by 18.3% ( P <.001) and 21.7% ( P <.001), respectively. FMD tended to increase in patients receiving pravastatin (0.7% ± 0.6%); however, the difference between treatment phases was not statistically significant ( P = .080). Conclusions This is the first double-blind, placebo-controlled study of the effects of statin therapy on lipids, lipoprotein subfractions, and endothelial function in patients taking HIV PIs. Pravastatin reduced concentrations of atherogenic lipoproteins, particularly those most associated with future coronary events.

Ritonavir and Saquinavir directly stimulate anterior pituitary prolactin secretion, in vitro.

An association between human immunodeficiency virus type I (HIV-1) protease inhibitors (PIs) and galactorrhoea/hyperprolactinemia adverse effect has recently been reported in four HIV-1-infected women treated with PIs (indinavir, nelfinavir, ritonavir or saquinavir). This could be explained by a direct effect of ritonavir and saquinavir on anterior pituitary prolactin (PRL) release, and/or an indirect effect of PIs on the secretion of hypothalamic dopamine, which is the main PRL inhibitory factor. Anterior pituitaries were explanted from adult male Wistar rats, the cells were trypsin dispersed, plated into multiwell cultures and incubated for 1 h with either ritonavir or saquinavir (0.01 nM-1μM). PRL release into the incubation medium was evaluated by radioimmunoassay. Hypothalamic neuronal endings (synaptosomes) were prepared by tissue homogenization, incubated with 3H-dopamine, substituting for the endogenous dopamine pool, and perfused with ritonavir or saquinavir, both basally and during depolarization (K+ 15 mM)-induced dopamine release. Beta-emission from 2 min perfusate fractions, corresponding to 3H-dopamine release, was detected by liquid scintillation scanning. We found that both ritonavir and saquinavir are able to significantly stimulate PRL secretion, with saquinavir slightly more effective than ritonavir. On the contrary, both protease inhibitors do not modify either basal or depolarization-induced dopamine release. We can speculate that HIV PIs despite a high affinity for the catalytic site of HIV protease, could also bind to and inhibit homologous mammalian proteins in the anterior pituitary that are involved in PRL secretion.