The synthesis and CysLT1 receptor affinities of a new series of highly rigid 3'- and 4'-(2-quinolinylmethoxy)- or 3'- and 4'-[2-(2-quinolinyl)ethenyl]-substituted, 6-, 7-, or 8-carboxylated flavones are described. CysLT1 receptor affinities of the flavones (down to 11 nM) were determined by their ability to displace [3H]LTD4 from its receptor in guinea pig lung membranes. Structure−affinity relationship studies showed that the relative positions of the carboxylic acid and the quinoline moiety were critical for CysLT1 affinities. While the carboxyl is optimal in the 8 position but tolerated in the 6 position, only the 6- and not the 8-tetrazole has significant activity. The quinoline moiety may be connected to the flavone skeleton by an ethenyl or a methoxy linker, but the substitution position is important for high affinity, especially in the 6-carboxylated flavones. 4'-Substituted 6-carboxyflavones are essentially inactive, whereas the 3'-substituted analogues have submicromolar CysLT1 affinity. Replacement of the quinoline by other heteroaromates generally leads to decreased affinities, with the phenyl and naphthyl analogues displaying only little or no affinity, while the 7-chloroquinoline analogue is comparable in activity to the quinoline. Flavones having CysLT1 receptor affinities of 10−30 nM were selected for determination of their inhibitory effects on the LTD4-induced contraction of guinea pig ileum in vitro. The IC50 values ranged between 15 and 100 nM. Compound 5d (8-carboxy-6-chloro-3'-(2-quinolinylmethoxy)flavone, VUF 5087) was selected for further research because of its high potency in the functional assay. This series contains the most rigid CysLT1 receptor antagonists known to date, and they are useful in the development of a CysLT1 antagonist model, which is discussed in the companion paper.
Background and aims: Familial Hypercholesterolemia (FH) is an inherited metabolic disorder with increased LDL-C levels and coronary heart disease (CHD) risk. The prevalence of heterozygous FH is approximately 1:200 to 1:500 worldwide and higher in CHD populations. We aim to estimate the prevalence of FH and the incidence of recurrent cardiovascular events among FH and non-FH patients in a large myocardial infarction cohort in China.
Methods: We studied the cohort from the China Patient-Centered Evaluative Assessment of Cardiac Events Prospective study (PEACE-Prospective). The eligible cohort included 3367 patients hospitalized for myocardial infarction (MI).
Results: The proportion of potential FH was 0.80% and 4.28% by Dutch Lipid Clinic Network (DLCN) and modified DLCN criteria, respectively. Compared to non-FH, the FH patients were younger, having more personal and family history of premature CHD, current smokers and overweight. The exome sequencing identified 11 cases of pathogenic variants on LDL receptor and ApoB. The risk of recurrent cardiovascular events after MI was greater in FH patients with a hazard ratio (HR) of 1.97 with modified DLCN.
Conclusions: The prevalence of Chinese FH by modified DLCN is comparable to the European estimate by DLCN in the high cardiovascular risk cohort. The patients with FH compared to non-FH have an almost 2-fold adjusted risk of recurrent cardiovascular events. Further consensus on the LDL-C-based threshold may help on the establishment of country specific criteria for FH.
ABSTRACT Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins are a group of naturally occurring cyclophilin binding polyketides that are structurally distinct from the cyclosporines and are produced by a microorganism amenable to biosynthetic engineering for lead optimization and large-scale production by fermentation. Preclinical characterization of the potential utility of this class of compounds for the treatment of HCV revealed that the natural sanglifehrins A to D are all more potent than CsA at disrupting formation of the NS5A-CypA, -CypB, and -CypD complexes and at inhibition of CypA, CypB, and CypD isomerase activity. In particular, sanglifehrin B (SfB) was 30- to 50-fold more potent at inhibiting the isomerase activity of all Cyps tested than CsA and was also shown to be a more potent inhibitor of the 1b subgenomic replicon (50% effective concentrations [EC 50 s] of 0.070 μM and 0.16 μM in Huh 5-2 and Huh 9-13 cells, respectively). Physicochemical and mouse pharmacokinetic analyses revealed low oral bioavailability ( F < 4%) and low solubility (<25 μM), although the half-lives ( t 1/2 ) of SfA and SfB in mouse blood after intravenous (i.v.) dosing were long ( t 1/2 > 5 h). These data demonstrate that naturally occurring sanglifehrins are suitable lead compounds for the development of novel analogues that are less immunosuppressive and that have improved metabolism and pharmacokinetic properties.
Leukotriene CysLT 1 receptor antagonists (also known as LfD4 antagonists) are among the most promising antiasthmatic agents currently under investigation. For the last 20 years there are many thousands of compounds prepared as CysLT 1 receptor antagonists and several of them have advanced to the clinical practice. The diverse chemical structures of CysLT 1 antagonists pose considerable difficulty in the identification of structural determinants for their activity. This review summarizes the structural modifications within each individual class of compounds and derives the general structural requirements for CysLT 1 antagonistic activity. Computer-aided rational design of CysL T 1 antagonists have been thoroughly analyzed and a new pharmacophoric model is presented to accommodate almost all SAR data experimentally observed. Since a stable and selective CysLT 1 receptor agonist would be a very useful pharmacological tool, especially for the characterization of receptor subtypes, the SARs of CysLT 1 agonists have also been discussed in the present paper. These information are also important for the understanding of ligand recognition of the CysLT 1 receptor.
Imaging conditions can not only affect the computational efficiency and storage cost of reverse time migration (RTM) but determine the quality of the final migrated images. This paper extends the idea of the well amplitude-preserved and highly-efficient excitation amplitude imaging condition from acoustic RTM to elastic RTM. For elastic RTM, the maximum amplitude of the separated P-wave and the corresponding image time of each grid point are saved during the forward modeling of the source wavefield and then PP and PS images are obtained by dividing the separated P- and S-waves of the backward-propagated receiver wavefield by the precomputed P-waves at each grid point that satisfies the image time. However, polarity reversals of the PS image will cause destructive interference when the stacked image is needed. In order to solve this problem, we propose the polarity-consistent excitation amplitude imaging condition by combining the excitation amplitude imaging condition with a shot-domain polarity reversal correction method. Then we provide the detailed realization process of this imaging condition in elastic RTM. By utilizing the relatively stable and well amplitude-preserved source-normalized cross-correlation imaging condition as a comparison, we testify to the feasibility and validity of the proposed imaging condition in the aspects of amplitude preservation property, imaging capability of complex structures, storage cost and computational efficiency. Considering the balance between the efficiency and image quality, the polarity-consistent excitation amplitude imaging condition can be a good choice for elastic RTM.
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