Open Medicinal Chemistry Journal最新文献

Multiple lines of evidence indicate that hypofunction of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia, suggesting that increasing NMDA receptor function via pharmacological manipulation could provide a new strategy for the management of schizophrenia. Currently, the glycine modulatory sites on NMDA receptors present the most attractive therapeutic targets for the treatment of schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory sites on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methyl glycine) shows antipsychotic activity in patients with schizophrenia. Accordingly, a number of pharmaceutical companies have developed novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. This paper provides an overview of the various GlyT-1 inhibitors and their therapeutic potential.

A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.

Three major flavonoid chamomile components (quercetin, apigenin-7-O-glucoside and rutin) were subjected to oxidative metabolism by cytochrome P-450 of rat liver microsomal preparations. Changes over time in their respective concentrations were followed using reversed-phase HPLC with UV detection. No clean-up had to be applied as only the specific flavonoid had to be separated from the background components originating from the rat liver microsome.Neither the concentration of apigenin-7-O-glucoside nor that of the diglycoside rutin decreased during one hour of exposure to rat microsomal treatment. In contrast, the concentration of quercetin, a lipophilic aglycon, decreased.Our analytical HPLC results complement the in silico calculated lipophilicity (logP) of these compounds; the relatively high lipophilicity of quercetin appears to predispose it to oxidative metabolism in order to decrease its fat solubility. In contrast the much less lipophilic compounds apigenin-7-O-glucoside and rutin were resistant in vitro to microsomal treatment.

A series of alkyl- and aryl-1,2,4-triazino[4,3-c]quinazolines (5a-h and 8a-h) were synthesized and characterized. The title compounds were evaluated for their in vivo bronchodilator activity on guinea pigs. All the test compounds exhibited good protection against histamine-induced bronchospasm. The structure-activity relationships based on the results obtained for these series were studied. Incorporation of an aryl ring with halo substitution to the theophylline bioisostere increases its potency. Among the compounds tested, 5b was found to be the most potent with 88.7% protection against histamine-induced bronchospasm compared to the standard compound aminophylline (87.8%).

In a brain-targeting prodrug approach for a metabolically stable enkephalin analogue DADLE, specific enzymes are utilized for in vivo prodrug activation. Prolyl oligopeptidase (POP) may be especially useful in this regard. In vitro metabolic stability of the putative metabolites of prodrugs having various "spacers" has shown that POP provides significantly faster release of DADLE from conjugates having dipeptidyl spacer (specifically Xaa-Pro or Xaa-Ala) than alternative peptidases utilized when single amino acids are used as spacers. In vitro half-lives measured in rat brain homogenate showed excellent correlation with CNS-mediated analgesia using the tail-flick model in rats providing, thus, an in vivo substantiation of the prodrug approach relying on POP as the peptidase to release DADLE.

Liver X receptor (LXR) is an attractive drug target for the development of novel therapeutic agents for the treatment of dyslipidaemia and cholestasis. In the present work, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent LXR ligands. Significant correlation coefficients (CoMFA, r(2) = 0.98 and q(2) = 0.69; HQSAR, r(2) = 0.99 and q(2) = 0.85) were obtained, indicating the potential of the models for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values obtained from the 2D and 3D models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D steric and electrostatic contour maps and 2D contribution maps should be useful for the design of novel LXR ligands having improved potency.

Streptozocin has been shown to be useful in the clinical treatment of malignant neuroendocrine tumors of the pancreas. The poor prognosis for patients having malignant tumors of pancreas suggests the investigation and development of new therapeutics. Nine analogs to streptozocin are determined by in silico physicochemical analysis and generation of structures by modeling from functional group isosteres. In these analogs is preserved the alkylating nitrosourea moiety, however, the covalently bonded substituent has significant hydrogen bonding sites and may include a ring structure. Analogs retain a broad range in lipophilicity, having a range of Log P from -2.798 (hydrophilic) to 3.001 (lipophilic). Standard deviation of molecular masses is only 12.6% of the group mean, so a small alteration in size occurs which is also reflected by only a 15.5% deviation in molecular volumes. Streptozocin and seven analogs show zero violations of the Rule of 5 which suggests favorable bioavailability. All compounds showed at least seven hydrogen bond acceptors with a strong positive correlation between hydrophilicity to the total number of hydrogen bond acceptors and donors. Analysis of similarity (ANOSIM) and discriminant analysis determined that streptozocin is highly similar to all nine analogs. However hierarchical cluster analysis and K-means cluster analysis were able to elucidate patterns of associations and differentiation among the ten compounds. This study demonstrates the efficacy of utilizing in silico optimization and pattern recognition to elucidate potential anticancer drugs.

In this study we investigated the structure-activity relationships by using the Electron- Topological Method (ETM) for a class of AChE inhibitors related to tacrine (9-amino-1,2,3,4-tetrahydroacridine) and 11 H-Indeno-[1,2-b]-quinolin-10-ylamine that tetracyclic tacrine analogues, a drug currently in use for the treatment of the AD. Molecular fragments being specific for active and inactive compounds were revealed by using ETM. The result of testing showed the high ability of ETM in predicting the activity and inactivity in investigated series.

(11)C-labeled carbamates can be obtained in a three-component coupling reaction of primary or secondary amines with CO(2) and (11)C-methylation reagents. [(11)C]Methyl-triflate mediated methylation of carbamino adducts provides the corresponding (11)C-labeled carbamate groups in excellent yields under mild conditions (temperatures

This work is focused on the ex vivo study of corneal permeation of two anti-inflammatory drugs: diclofenac, and flurbiprofen (as a model of hydrophilic and lipophilic drug, respectively) loaded to cyclodextrins or polymeric nanoparticles in order to determine differences in their corneal permeation against free drug or commercial eye drops. These studies were carried out in a corneal device designed and developed in our laboratory. In this work the habitual conditions for the permeation studies were modified to reproduce the behaviour when eye drops were administered. For this reason a new tetracompartmental pharmacokinetic model was developed. The complex formation of diclofenac with cyclodextrins and the flurbiprofen loaded to polymeric nanoparticles has been shown as effective procedures to remarkably increase the bioavailability of the anti-inflammatory drugs. The efficiency of polymeric nanoparticles of Poly (D-L lactic-coglycolyc) acid and poly-epsilon-caprolacton as intraocular targeting of NSAIDs has also been proved, being the latter polymer more effective to increase the flurbiprofen corneal permeation. The apparent corneal permeability coefficient of samples has been calculated getting a low permeation values for free drugs.