Asymmetric synthesis and evaluation of epoxy-α-acyloxycarboxamides as selective inhibitors of cathepsin L.

Cathepsin L plays important roles in physiological processes as well as in the development of many pathologies. Recently the attentions were turned to its association with tumor progress what makes essential the development of more potent and selective inhibitors. In this work, epoxipeptidomimetics were investigated as new cathepsin inhibitors. This class of compounds is straightforward obtained by using a green one-pot asymmetric epoxidation/Passerini 3-MCR. A small library of 17 compounds was evaluated against cathepsin L, and among them LSPN423 showed to be the most potent. Investigations of the mechanism suggested a tight binding uncompetitive inhibition.

Immobilized cholinesterases capillary reactors on-flow screening of selective inhibitors.

The discovery of selective inhibitors for acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) is extremely important for the development of drugs that can be used in the treatment of patients diagnosed with the Alzheimer's disease (AD). For this reason, there is a growing interest in developing rapid and effective assays techniques for cholinesterases (ChE) enzymes ligand screening. Herein is presented the results of selective screening assays of a coumarin derivatives library using BChE and AChE covalently immobilized onto silica fused capillaries (ICERs, 15 cm × 0.1 mm ID). The statistical comparison of the ICERs screening assay with that of the free enzymes is reported and highlights the advantages of the on-flow ICERs assay. Two out of 20 coumarin derivatives could be highlighted: compound 17 is more active toward BChE (IC50=109 ± 21 µM) and 19 showed activity against both enzymes (BChE IC50=128 ± 28 µM and hu-AChE IC50=144 ± 40 µM). The statistical evaluation of the results of the ICERs and free enzyme assays showed no difference between them, further validating the ICERs assay model. The ICERs ability to recognize selective ligands and its use for characterization of the inhibition mechanisms of the hits consolidates the approach here reported.

Enantioselective disposition of omeprazole, pantoprazole, and lansoprazole in a same Brazilian subjects group.

This work reports the result of the enantioselective disposition of pantoprazole, omeprazole, and lansoprazole in a same group of Brazilian health subjects. Ten nongenotyped healthy subjects were used for this study. Each subject received a single oral dose of 80 mg of pantoprazole, 40 mg of omeprazole, and 30 mg of lansoprazole, and the plasma concentrations of the enantiomers were measured for 8 h postdose. For pantoprazole and omeprazole, among the 10 volunteers investigated, only one volunteer (Subject # 4) presented higher plasma concentrations of the (+)-enantiomer than those of (-)-enantiomer. Nevertheless, the area under the concentration-time curve of the (+)-lansoprazole was higher than those the (-)-lansoprazole for all subjects. The comparison of proton pump inhibitors' enantiomers disposition from a single group volunteer demonstrated that pantoprazole and omeprazole can be used to differentiate extensive from poor CYP2C19 metabolizer while lansoprazole cannot do it.

Bioequivalence of two enteric coated formulations of pantoprazole in healthy volunteers under fasting and fed conditions.

PURPOSE: To compare the bioavailability of two pantoprazole (CAS 102625-70-7) formulations (40 mg pantoprazole enteric coated tablets) under fasted and fed conditions as well as to evaluate the dissolution profile in biorelevant media. METHODS: The subjects received either 40 mg of the reference or of test formulation in fasting (n = 28) and fed (n=70) condition. The studies were conducted according to a single dose and randomized crossover design. Blood samples were collected up to 12 h after drug administration in fasting condition and up to 48 h in fed condition. Plasma concentrations of pantoprazole were determined by LC-MS/MS. Pharmacokinetic parameters were calculated from the observed plasma concentration-time profiles. Bioequivalence between the formulations in fasting and fed condition was assessed considering 90% confidence intervals for the ratio of means for lnCmax and lnAUC(0-t) within 0.8-1.25. Dissolution profiles were evaluated in biorelevant media [Fasting State Simulating Intestinal Fluid (FaSSIF) and Fed State Simulating Intestinal Fluid (FeSSIF)]. The sameness of the dissolution curves was assessed by f2 values between 50 and 100. RESULTS: Under fasting condition the 90% confidence interval for the ratio of means for the lnCmax, (0.94-1.03) and lnAUC(0-t) (0.89-0.99) was within the guideline range of bioequivalence (0.80-1.25). However, the data for lnCmax (0.51-0.76) and lnAUC(0-t) (0.68-0.90) under fed condition were not within the bioequivalence range. The postprandial study demonstrated a high intra-subject variability and in some subjects pantoprazole could not be detected for up to 24 h, although the dissolution profile of reference and test formulations presented a similar disposition in FaSSIF and FeSSIF as confirmed by the values of f2 higher than 50. CONCLUSION: The results demonstrated that the test formulation was bioequivalent to the reference in fasting condition but not in postprandial state. The dissolution profile in FaSSIF indicates that this biorelevant medium was more adequate to discriminate the in vivo disposition of pantoprazole than FeSSIF. Furthermore, the fed condition study had shown a pronounced influence of food in the absorption of pantoprazole after single oral dose administration.