The changing face of oral anticoagulants.

Warfarin has been the established oral anticoagulant for the last 50 years, being effective in the prevention and treatment of venous and arterial thromboembolic disorders. However, the frequent requirement for INR monitoring, multiple drug and food interactions have fuelled the need for development of new oral anticoagulants. Dabigatran is the first of a series of new oral anticoagulants that are emerging as the successors to warfarin. This new group of anticoagulants is rapidly gaining FDA and NICE approval and has proven non-inferiority to warfarin and viable alternatives to warfarin in the coming years. Given the obvious impact of this on dental treatment in the primary care and hospital setting this article aims to increase familiarisation with this new medicine group.

An overview of the preclinical toxicity and potential carcinogenicity of sitaxentan (Thelin®), a potent endothelin receptor antagonist developed for pulmonary arterial hypertension.

Sitaxentan (Thelin®), an endothelin receptor antagonist with a long duration of action and high specificity for the endothelin receptor A subtype, was used to treat pulmonary arterial hypertension. It was withdrawn from the market due to an idiosyncratic risk of drug-induced liver injury identified from emerging clinical trial data and clinical case reports. The preclinical safety profile of sitaxentan is presented, including single- and repeat-dose toxicity in mice, rats, and dogs and carcinogenicity in mice and rats. Sitaxentan-related adverse effects included coagulopathy in rats and dogs, increased serum alkaline phosphatase activity in mice and dogs, and hepatic hypertrophy in all species. Decreased albumin, erythrocyte count, hemoglobin concentration and hematocrit, and increased coagulation times and liver weight were also noted. These effects generally occurred at systemic exposures (AUC(0-24)) that were substantially greater than those seen in humans. Twice-daily (vs. once daily) dosing resulted in increased toxicity, which correlated with increased trough plasma sitaxentan concentrations. Sitaxentan appeared to have a low potential for testicular and hepatic toxicity and was not carcinogenic. These studies suggested that sitaxentan would have a reasonable margin of safety when used as directed in humans and supported a positive benefit:risk assessment at the time of marketing approval.

Characterization of two classes of small molecule inhibitors of Arp2/3 complex.

Polymerization of actin filaments directed by the actin-related protein (Arp)2/3 complex supports many types of cellular movements. However, questions remain regarding the relative contributions of Arp2/3 complex versus other mechanisms of actin filament nucleation to processes such as path finding by neuronal growth cones; this is because of the lack of simple methods to inhibit Arp2/3 complex reversibly in living cells. Here we describe two classes of small molecules that bind to different sites on the Arp2/3 complex and inhibit its ability to nucleate actin filaments. CK-0944636 binds between Arp2 and Arp3, where it appears to block movement of Arp2 and Arp3 into their active conformation. CK-0993548 inserts into the hydrophobic core of Arp3 and alters its conformation. Both classes of compounds inhibit formation of actin filament comet tails by Listeria and podosomes by monocytes. Two inhibitors with different mechanisms of action provide a powerful approach for studying the Arp2/3 complex in living cells.

Classification structure-activity relationship (CSAR) studies for prediction of genotoxicity of thiophene derivatives.

The grid search support vector machine (GS-SVM) was used to build a classification structure-activity relationship (CSAR) model and to predict the genotoxicity property of 140 thiophene derivatives with the information derived from the compounds' molecular structures. The seven descriptors selected by linear discriminant analysis (LDA) were used as the inputs to develop the GS-SVM model. Using the Grid Search method, a satisfactory model with a good predictive capability was obtained. The quality of the models was evaluated by the number of right classified compounds. The total accuracy of the LDA model was 81.4% and 85.2% for the training set and test set, respectively, and to the GS-SVM model was 92.9% and 92.6%, respectively. It was proved that the GS-SVM method was a very useful modeling approach with good classification ability for the genotoxicity of the thiophene derivatives. This work also provides a new idea and an alternative method to investigate the genotoxicity of the similar structures with thiophene derivatives, and can be extended to other toxicity studies.

Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family.

AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis. Activation of AMPK in peripheral tissues has been shown to alleviate the symptoms of metabolic diseases, such as type 2 diabetes, and consequently AMPK is a target for treatment of these diseases. Recently, a small molecule activator (A-769662) of AMPK was identified that had beneficial effects on metabolism in ob/ob mice. Here we show that A-769662 activates AMPK both allosterically and by inhibiting dephosphorylation of AMPK on Thr-172, similar to the effects of AMP. A-769662 activates AMPK harboring a mutation in the gamma subunit that abolishes activation by AMP. An AMPK complex lacking the glycogen binding domain of the beta subunit abolishes the allosteric effect of A-769662 but not the allosteric activation by AMP. Moreover, mutation of serine 108 to alanine, an autophosphorylation site within the glycogen binding domain of the beta1 subunit, almost completely abolishes activation of AMPK by A-769662 in cells and in vitro, while only partially reducing activation by AMP. Based on our results we propose a model for activation of AMPK by A-769662. Importantly, this model may provide clues for understanding the mechanism by which AMP leads to activation of AMPK, which in turn may help in the identification of other AMPK activators.

Speciation of alkylated dibenzothiophenes through correlation of structure and gas chromatographic retention indexes.

The gas chromatographic (GC) speciation of polycyclic aromatic sulfur heterocycles (PASH) in deeply desulfurized fuels is difficult without recourse to authentic standard compounds. Here we investigate the GC retention indexes for 30 alkylated dibenzothiophenes on two methylphenylsiloxane stationary phases of different selectivity (5% and 50% phenyl groups) with a view to avoid the synthesis of all congeners. The influence of the substitution pattern on the retention indexes is discussed. With the measured data it is possible to carry out a multiple linear regression (MLR) to calculate parameters for predicting the retention indexes of unknown polymethylated isomers based only on their structural features. Nine trimethyldibenzothiophene in a synthesis product are identified through their retention indexes. The retention indexes for a total of 43 alkyldibenzothiophenes are listed.

Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor.

A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice).

Molecular analysis of arylalcohol dehydrogenase of Coriolus versicolor expressed against exogenous addition of dibenzothiophene derivatives.

Using the differential display reverse-transcriptional polymerase chain reaction (DDRT-PCR) technique, several cDNA fragments were isolated as chemical stress responsive genes from the white-rot basidiomycete, Coriolus versicolor, exposed to either 4-methyldibenzothiophene-5-oxide (4MDBTO) or dibenzothiophene-5-oxide (DBTO). A database search on deduced amino acid sequences of cDNAs revealed that they showed a high similarity with various proteins from other organisms. These results strongly suggested that cell responding systems might be involved in the fungal metabolism of exogenous chemicals by C. versicolor. One of the significantly up-regulated cDNA fragments by MDBTO, DD16gc, showed a high similarity to arylalcohol dehydrogenases (AADs) from several microorganisms. The full-length cDNA sequence of the DD16gc determined by 5' rapid amplification of cDNA ends method revealed that the gene consisted 1,295 nucleotide and poly(A) tail, encoding 394 amino acids in an open reading frame. The deduced protein showed a remarkable homology to AAD from Phanerochaete chrysosporium (66% identity) and to that from Saccharomyces cerevisiae (54% identity). The AAD gene was specifically transcripted under chemically-stressed conditions by 4MDBTO, suggesting that the enzyme encoded by the stress responsive gene may play an important role in the fungal conversion of 4MDBTO or its metabolic product(s).