Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase

The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes

Preparation of Novel 3H-Trifluoromethyldiazirine-Based Photoactivatable Potassium Channel Antagonists.

The preparation of a series of photoactivatable precursors for use in photoaffinity labelling of potassium channels is described. 3H-Diazirine functionalities were incorporated into the previously described potassium channel antagonists 1-3. The ability to perform enantioselective reductions and Wittig reactions in the presence of 3H-diazirines was central to this work. (c) 2005 Elsevier Ltd. All rights reserved

An Efficient Route To S-N-(9-Fluorenylmethoxycarbonyl)-4'-(1-Azi-2,2,2-Trifluoroethyl)phenylalanine

An extremely efficient synthesis of optically pure photoactivatable phenylalanine derivative 1 is described. The key step involves a highly diastereoselective alkylation of a chiral glycine equivalent

The synthesis and reactivity of optically pure amino acids bearingside-chain thioamides

The synthesis and reactivity of fully protected thioamide analogues of asparagine: and glutamine are described. A key feature of the synthetic strategies employed was the ability to perform selective thiations on multiple carbonyl-containing substrates. Also described are the preparations of thioamide derivatives of phenylalanine. The utility of these amino acid derivatives for solid-phase peptide synthesis is discussed

Essential dynamics of the cellular retinol-binding protein - Evidence for ligand-induced conformational changes

The cellular retinol-binding protein (CRBP) is an intracellular retinol carrier protein belonging to a family of hydrophobic ligand-binding proteins, It transports retinol to specific locations in the cell where, for instance, it is esterified for storage, Recently solved crystallographic structures of CRBP homologues with and without bound ligand do not provide evidence for a ligand-induced conformational change, However, it has been shown that there is a difference in binding of holo-CRBP and apo-CRBP to lecithin-retinol acyltransferase, Moreover, proteolysis of holo-CRBP and apo-CRBP yields different products, indicating a difference in structure or dynamics between the two forms, Here, we present the results of molecular dynamics simulations of holo-CRBP and apo-CRBP, The simulations show a significant difference in conformation, in agreement with experimental results, The essential dynamics method was used to study differences in dynamics between the apo and hole forms of CRBP, and showed inhibition of essential motions upon ligand binding, It also revealed large correlated motions of retinol with regions of the protein, pointing to a possible retinol entry/exit site