Pyrido4,3-dpyrimidin-4(3H)-one (1) was prepared by reacting 2-trifluoromethyl-4-iodo-nicotinic acid (2) with amidine 9a catalyzed by Pd(2)(dba)(3) and Xantphos, followed by cyclization effected with ...HBTU and subsequent demethylation using PhBCl(2). The amidine arylation method was found applicable for the syntheses of quinazolin-4(3H)-ones. Thus, reaction of 2-bromo or 2-iodo benzoate esters with amdidines afforded substituted quinazolin-4(3H)-ones in 44-89% yields.
Cholesteryl ester transfer protein (CETP) shuttles various lipids between lipoproteins, resulting in the net transfer of cholesteryl esters from atheroprotective, high-density lipoproteins (HDL) to ...atherogenic, lower-density species. Inhibition of CETP raises HDL cholesterol and may potentially be used to treat cardiovascular disease. Here we describe the structure of CETP at 2.2-A resolution, revealing a 60-A-long tunnel filled with two hydrophobic cholesteryl esters and plugged by an amphiphilic phosphatidylcholine at each end. The two tunnel openings are large enough to allow lipid access, which is aided by a flexible helix and possibly also by a mobile flap. The curvature of the concave surface of CETP matches the radius of curvature of HDL particles, and potential conformational changes may occur to accommodate larger lipoprotein particles. Point mutations blocking the middle of the tunnel abolish lipid-transfer activities, suggesting that neutral lipids pass through this continuous tunnel.
Biocatalytic reductive amination catalyzed by engineered imine reductase (RedAms) is a new and powerful tool for the synthesis of substituted chiral amines. Herein, we describe a streamlined ...synthesis of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxyketone to introduce the chiral secondary amine with high diastereoselectivity. The improved synthesis of the hydroxyketone precursor by a titanium-catalyzed reductive cyclization and the process development for two SNAr reactions en route to 3 are also presented.
Process development for the synthesis of a second generation β-amyloid-cleaving enzyme (BACE1) inhibitor (1) is described. The lithiothiazole addition to the isoxazolene (5) under batch conditions ...was not scalable because of reaction gelling and anion instability. A continuous stirred-tank reactor flow process was developed and successfully executed on the 70 kg scale in multiple runs. In a head-to-head comparison between the continuous and batch processes, the former was clearly superior as it gave a higher yield (80 vs 63%) of the adduct (4) and better reaction control for handling the unstable lithiothiazole as a reaction intermediate. Subsequently, 4 underwent Pd-catalyzed amination with t-butyl carbamate, reductive cleavage of the N–O bond, thioamidine cyclization, and deprotection of the Boc group to provide hydropyranothiazine 2. The synthesis of 1 was completed by amidation with 5-(difluoromethoxy)picolinic acid and the successive deprotection of the benzamide group with either Silicycle-diamine or l-lysine.
The arm swing in hockey skating can have a positive effect on the forces produced by each skate, and the resulting velocity from each push off. The main purpose of this study was to measure the ...differences in ground reaction forces (GRFs) produced from an anteroposterior versus a mediolateral style hockey skating arm swing. Twenty-four elite-level female hockey players performed each technique while standing on a ground-mounted force platform, and all trials were filmed using two video cameras. Force data was assessed for peak scaled GRFs in the frontal and sagittal planes, and resultant GRF magnitude and direction. Upper limb kinematics were assessed from the video using Dartfish video analysis software, confirming that the subjects successfully performed two distinct arm swing techniques. The mediolateral arm swing used a mean of 18.38° of glenohumeral flexion/extension and 183.68° of glenohumeral abduction/adduction while the anteroposterior technique used 214.17° and 28.97° respectively. The results of this study confirmed that the mediolateral arm swing produced 37% greater frontal plane and 33% less sagittal plane GRFs than the anteroposterior arm swing. The magnitudes of the resultant GRFs were not significantly different between the two techniques; however, the mediolateral technique produced a resultant GRF with a significantly larger angle from the direction of travel (44.44°) as compared to the anteroposterior technique (31.60°). The results of this study suggest that the direction of GRFs produced by the mediolateral arm swing more closely mimic the direction of lower limb propulsion during the skating stride.
The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part ...by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after short- and long-term treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the down-regulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism, suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Whereas these compounds are efficacious in acute preclinical models, extended safety studies and further clinical testing will be required before the full therapeutic promise of a selective PPARalpha agonist is realized.
Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped ...operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage and waste stream volume over the first scale-up campaign. Particular highlights of this effort include the development of an efficient synthesis of 3-hydroxy-1,5-naphthyridine-4-carbaldehyde via a Skraup process and engineering a robust final API synthesis. We also discovered a crystalline monotosylate salt that addressed significant formulation and degradation issues experienced when using the noncrystalline freebase.
Radical fluoroalkylation is a powerful synthetic tool for the late-stage incorporation of fluorinated moieties into organic molecules, which is widely used in the development of pharmaceuticals and ...agrochemicals. Here, we report an efficient radical chlorodifluoromethylation protocol with sodium chlorodifluoromethanesulfinate, which is complementary to the existing late-stage difluoromethylation strategies. CF2Cl radical is a suitable surrogate for accessing the CF2H group while possessing completely different electronic properties compared to the CF2H radical. This method is chemoselective and regioselective for the chlorodifluoromethylation of (hetero)arenes and electron-rich alkenes and shows good functionality, tolerance, and generality on scope. The preparation of the sodium chlorodifluoromethanesulfinate is thoroughly investigated and can be scaled up to hundreds of kilograms. The method is successfully implemented on the synthesis of an oncology candidate compound 1.
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A new radical chlorodifluoromethylation reagent (ClCF2SO2Na) is disclosedThe CF2Cl radical is a suitable surrogate for accessing the CF2H groupThe reaction is chemo- and regioselective for (hetero)arenes and electron-rich alkenesThe preparation of the sodium chlorodifluoromethanesulfinate is developed
Meng et al. develop a radical chlorodifluoromethylation protocol using ClCF2SO2Na as a chlorodifluoromethyl radical precursor. The CF2Cl radical is an electrophilic surrogate for the nucleophilic CF2H radical. This method is chemoselective and regioselective for the chlorodifluoromethylation of (hetero)arenes and electron-rich alkenes and is applied in the difluoromethylation of an oncology candidate.
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