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The pharmacokinetics of a series of novel cyclic, non-peptide inhibitors of HIV protease were studied in rats or dogs after intravenous and oral administration. Six symmetrically substituted cyclic urea compounds (XK234, XM311, XM320, XM321, XM323, and XM412), which effectively inhibited HIV virus replication, with IC90 values of 0.03-1.0 microM (0.017-0.76 microgram mL-1), were evaluated. Plasma concentrations were measured in rats and dogs using specific and sensitive HPLC methods. In rats, the maximum plasma concentrations of 0.21-1.88 micrograms mL-1 were detected within 1 h of oral administration of 10 mg kg-1 of the compounds. The elimination half-lives ranged from 1.25 to 3.3 h in rats and the absolute oral bioavailability ranged from 18 to 100%. In dogs, the maximum plasma concentration and absolute oral bioavailability were 4.37 micrograms mL-1 and 48%, 1.07 micrograms mL-1 and 16%, and 1.48 mg ML-1 and 38% for XK234, XM311, and XM323, respectively. The data demonstrated that the maximum plasma concentrations of these cyclic ureas were several times higher than the IC90 for inhibition of viral replication after single doses of 10 mg kg-1 in rats and dogs. With this combination of high potency against virus replication and good oral bioavailability, these cyclic ureas represent a new class of compounds that are suitable for development as therapeutic agents for the treatment of HIV-associated diseases.

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DuP 532, 2-propyl-4-pentafluoroethyl-1-([2'-(1H-tetrazol-5-yl)biph eny l-4-]methyl) imidazole-5-carboxylic acid, is an orally active, non-peptide angiotensin II (AII) receptor antagonist. DuP 532 is more potent and longer acting than losartan, another AII receptor antagonist currently undergoing phase III clinical trials. The pharmacokinetics and the effect of the salt form on the bioavailability of DuP 532 were determined in rats and dogs. In rats, the absolute oral bioavailability and half-life averaged 8.0% and 3.5 h, respectively, after the sodium bicarbonate solution and 7.6% and 3.6 h, respectively, after the methyl cellulose suspension. In dogs, the absolute oral bioavailability averaged 13.4% after the sodium bicarbonate solution and 11.9% after hard gelatin capsules containing the neat powder. The data demonstrated that there were no differences in bioavailability between the free acid and the sodium salt of DuP 532 after oral administration to rats and dogs. The in vitro metabolism of 14C-DuP 532 was evaluated with rat, dog, and human liver microsomes. HPLC analyses with UV and radiochemical flow detection showed that recovery of DuP 532 was greater than 99%, suggesting that there was little if any metabolism by liver microsomal enzymes. Therefore, the low oral bioavailability in rats was probably due to poor absorption of DuP 532 from the GI tract rather than extensive metabolism.

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EXP631, 4-(3-thienyl)-alpha, alpha,1-trimethyl-4-piperidine-methanol hemi-fumarate salt (I), is a centrally acting non-opioid analgesic compound with monoamine uptake blocking properties. EXP631 has analgesic effects in several animal models. It is intended to be used for the treatment of moderate to moderately severe acute and chronic pain. To characterize the disposition of EXP631, the plasma levels of EXP631 were determined in rats and dogs after single intravenous and oral doses. In rats, EXP631 was rapidly absorbed following a single oral solution dose of 5-20 mg kg-1 with maximum plasma levels detected within 1.2 h post dose. The absorption was complete with an oral bioavailability of 92-131%. The pharmacokinetics was dose independent as measured by either Cmax or AUC values. In fasted dogs, EXP631 was absorbed rapidly and well (F = 81%) from an oral solution with the maximum concentration detected at 20 min post dose. In fed dogs, the absorption from capsules was slower (1.38 h) compared to the solution, but the absorption was complete (F = 115%). An N-desmethyl metabolite (II) was found in both rat and dog plasma samples. The structure was confirmed by mass spectroscopy, nuclear magnetic resonance spectroscopy and comparative chromatographic retention times. The metabolite is inactive as an analgesic.