Leukotrienes (LTs)
are proinflammatory mediators derived from arachidonic
acid (AA), which play significant roles in inflammatory diseases.
The 5-lipoxygenase-activating protein (FLAP) is an integral membrane
protein, which is essential for the initial step in LT biosynthesis.
The aim of this study was to discover novel and chemically diverse
FLAP inhibitors for treatment of inflammatory diseases requiring anti-LT
therapy. Both ligand- and structure-based approaches were applied
to explain the activities of known FLAP inhibitors in relation to
their predicted binding modes. We gained valuable insights into the
binding modes of the inhibitors by molecular modeling and generated
a multistep virtual screening (VS) workflow in which 6.2 million compounds
were virtually screened, and the molecular hypotheses were validated
by testing VS-hit compounds biologically. The most potent hit compounds
showed significant inhibition of FLAP-dependent cellular LT biosynthesis
with IC50 values in the range from 0.13 to 0.87 μM.
Collectively, this study provided novel bioactive chemotypes with
potential for further development as effective anti-inflammatory drugs.
Dibenzo- and benzindolo-azecines represent a class of potential neuroleptics. To characterize the effectiveness at the dopamine and 5-HT-receptor representative structures were synthesized and tested by radio ligand binding studies, in vivo and in vitro studies.Neuroleptic potency and the risk of side effects of the prodrug 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-yl isobutyrate, an ester derivative of the most promising azecine 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404), was tested in vivo concerning conditioned avoidance response inhibition, locomotor activity and triggering of catalepsy vs. haloperidol as a reference. Also ester hydrolysis was examined using porcine liver esterase to thereby obtain an indication of the stability of the prodrug in vivo. An HPLC method was developed for purity control and determination of octanol/water-distribution coefficients.It has been shown that the tested substances in their efficacy are comparable to haloperidol and risperidone, but the therapeutic index in most cases is larger. Esterification as a prodrug principle leads to significantly prolonged effectiveness.
Dibenzoazecines are a new class of drug candidates for the treatment of schizophrenia. Compared to the drugs currently used in therapy, the azecines have a novel mechanism of action. Thus, they have the potential to cause fewer side effects compared to the standard therapy with a constant high neuroleptic potency. This theory was substantiated by comparative in vivo tests with haloperidol and risperidone. Seventeen new azecine derivatives have already been tested furthermore of stability, physicochemical parameters, pharmacokinetics including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH values and determination of octanol/water-partition coefficients. For these substances, class is still a lack of information concerning the metabolism. Therefore, the present study investigated and developed a reliable and reproducible gradient reversed-phase HPLC–UV method to determinate the lead structure LE404 alongside emerging metabolites in compliance with international requirements like ICH guidelines and the European Pharmacopoeia. Up to now, there is no innovative method suitable for such a determination. Chromatographic separations were achieved with a phenomenex™ Gemini column (5 µm C18 110 Å, 250 × 4.60 mm) using a mixture of acetonitrile/potassium dihydrogen phosphate buffer (4 mmol L−1, pH 2.5) as mobile phase. The gradient method flow rate was 1.0 mL min−1, and UV detection was made at 220 nm. The optimized HPLC method was found to be specific, accurate, reproducible and robust for determination of LE404.
Dibenzoazecines are a class of potential neuroleptics with high affinity to dopamine and serotonin receptors. The efficacy and high therapeutic range has already been demonstrated in vivo with the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404: ) and selected derivatives. There is a variety of new synthesized structurally different dibenzoazecine derivatives with the aim to improve pharmacokinetic parameters, all of which contain the lead structure LE404: . For a multitude of these substances is still a lack of information, inclusive of stability, physicochemical parameters, pharmacokinetics and metabolism. Therefore, the present study investigated the stability properties of 17 new azecine derivatives, including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH-values and determination of octanol/water-partition coefficients. These findings, in correlation to the properties and efficacy of the already in vivo tested substances, will be useful for safety and efficacy in further in vivo tests.
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