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A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.

Efficient and applicable approach to macrolactonizations, with ready availability of starting materials and simple operation, remains a challenging task for the organic community. We developed a ‘freshman-can-do’ protocol to medium- and large-sized lactones, not depending on high-dilution or slow addition techniques. Application of this method for the synthesis of natural lactones or potentially pharmaceutical compounds might be useful for organic chemists and pharmacists.

The synthesis of polysubstituted oxazolines is of great interest due to the synthetic and pharmaceutical importance. We developed a sequence of Pummerer/Michael reactions for the stereoselective synthesis of 5-(1-(arylthio)vinyl)-oxazolines.

A process of depolymerization of a new fucosylated chondroitin sulphate from Thelenata ananas by free-radicals was developed. The fractions with different molecular weights and a narrow molecular weight distribution was obtained. The products were characterised by physicochemical properties, FT-IR spectra and NMR spectra. The results confirm the retention of primary structure of the fractions after the depolymerization. Furthermore, the anticoagulant activity of the fractions was evaluated by the activated partial thromboplastin time (APTT). The APTT activity decreases in proportion to the molecular weight following a logarithmic-like function, and the potentiating of prolongation of APTT activity requires at least an oligosaccharide chain of about 6–8 units (6000–7000 Da). Compared to high doses of low molecular weight heparin (LMWH), a more desirable molecular weight fraction (13,950 Da) demonstrates significantly lower anticoagulant activity. Thus, the fraction has more potential as an antithrombotic agent with reduced bleeding risk relative to LMWH.

The p38 mitogen-activated protein kinase (MAPK) is a central signaling molecule in many proinflammatory pathways, regulating the cellular response to a multitude of external stimuli including heat, ultraviolet radiation, osmotic shock, and a variety of cytokines especially interleukin-1beta and tumor necrosis factor alpha. Thus, inhibitors of this enzyme are postulated to have significant therapeutic potential for the treatment of rheumatoid arthritis, inflammatory bowel disease, osteoporosis, and many other diseases where aberrant cytokine signaling is the driver of disease. Herein, we describe a novel class of 3-amino-7-phthalazinylbenzoisoxazole-based inhibitors. With relatively low molecular weight, these compounds are highly potent in enzyme and cell-based assays, with minimal protein shift in 50% human whole blood. Compound 3c was efficacious (ED 50 = 0.05 mg/kg) in the rat collagen induced arthritis (CIA) model.

c-Met is a receptor tyrosine kinase that plays a key role in several cellular processes but has also been found to be overexpressed and mutated in different human cancers. Consequently, targeting this enzyme has become an area of intense research in drug discovery. Our studies began with the design and synthesis of novel pyrimidone 7, which was found to be a potent c-Met inhibitor. Subsequent SAR studies identified 22 as a more potent analog, whereas an X-ray crystal structure of 7 bound to c-Met revealed an unexpected binding conformation. This latter finding led to the development of a new series that featured compounds that were more potent both in vitro and in vivo than 22 and also exhibited different binding conformations to c-Met. Novel c-Met inhibitors have been designed, developed, and found to be potent in vitro and in vivo.

This paper proposes a modified operation mode of batch extractive distillation with two reboilers. The separation of ethanol and water using as ethylene glycol is well done to validate the feasibility of this mode. The pilot-plant experimental data under the identical operational conditions between the regular mode and the modified mode are in particular discussed. The studied results prove more practical advantages of the modified mode over the regular mode such as easier operation control, more flexibility and higher separation efficiency etc. So it supplies certain guidance for the industrial application of batch extractive distillation process.

Based on a putative binding mode of quizartinib (AC220, 1), a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor in Phase III clinical development, we have designed de novo a simpler aminopyridine-based hinge binding motif. Further optimization focusing on maximizing in vivo efficacy and minimizing CYP3A4 time-dependent inhibition resulted in a highly efficacious compound (6s) in tumor xenograft model for further preclinical development.

A thiazole derivative, 2-(2,6-dichlorobenzyl)-N-(4-isopropylphenyl) thiazole-4-carboxamide (1), was identified as a TRPV1 antagonist. We synthesized various thiazole analogs and evaluated them for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. The IC50 values of the most potent antagonists were ca. 0.050 μM in these assays.

The biological activity for a set of melanocortin-4 receptor (MC4R) agonists containing a piperazine core with an ortho-substituted aryl sulfonamide is described. Compounds from this set had binding and functional activities at MC4R less than 30 nM. The most selective compound in this series was >25,000-fold more potent at MC4R than MC3R, and 490-fold more potent at MC4R than MC5R. This compound also reduced food intake after oral dosing at 25, 50, and 100 mg kg−1 in fasted mice.

Novel αvβ3 antagonists based on the N-aryl-γ-lactam scaffold were prepared. SAR studies led to the identification of potent antagonists for αvβ3 receptor with excellent selectivity against the structurally related αIIbβ3 receptor. Additional interactions of N-aryl-γ-lactam derivatives with αvβ3 were found when compared to c(-RGDf[NMe]V-) peptide antagonist. The effects of the conformation and configuration of the γ-lactam core on the binding were also assessed.

A glycosaminoglycan from sea cucumber Thelenata anana (THG) was isolated as a polymer of molecular weight of around 70 kDa. Its low molecular weight derivatives were first prepared by free radical depolymerization with hydrogen peroxide in the presence of copper(II) ion. The parameters of the process were investigated by a high-performance gel permeation chromatography. Analyses of chemical composition and molecular weight distribution indicated that the fragmentation of the main-chain of THG occurred randomly, obeyed pseudo first-order kinetics, and produced species with rather narrow and unimodal distribution of molar mass. The characterization of different molecular weight fractions was investigated by using viscometry and atomic force microscopy (AFM). Analysis of molecular weight and intrinsic viscosity in terms of the known theories for unperturbed wormlike cylinder yielded 1201 ± 110 nm −1 , 15.3 ± 1.5 nm, and 1.5 ± 0.3 nm for molar mass per unit contour length M L , persistence length q , and diameter d , respectively. The M L and d values were approximately consistent with those observed by AFM. The present data suggest that THG may dissolve in 0.1 M aqueous NaCl as single-stranded helical chains.

A novel class of pyrazolopyridazine p38α mitogen-activated protein kinase (MAPK) inhibitors is disclosed. A structure activity relationship (SAR) investigation was conducted driven by the ability of these compounds to inhibit the p38α enzyme, the secretion of TNFα in a LPS-challenged THP1 cell line and TNFα-induced production of IL-8 in the presence of 50% human whole blood (hWB). This study resulted in the discovery of several inhibitors with IC50 values in the single-digit nanomolar range in hWB. Further investigation of the pharmacokinetic profiles of these lead compounds led to the identification of three potent and orally bioavailable p38α inhibitors 2h, 2m, and 13h. Inhibitor 2m was found to be highly selective for p38α/β over a panel of 402 other kinases in Ambit screening, and was highly efficacious in vivo in the inhibition of TNFα production in LPS-stimulated Lewis rats with an ED50 of ca. 0.08 mg/kg.

Electrochemical scanning tunneling microscopy (EC-STM) has been applied to study the structure of the film formed by fusion of cholesterol suspensions and mixed dimyristoylphosphatidylcholine (DMPC)/cholesterol vesicles on a Au(111) electrode surface. It has been demonstrated that cholesterol molecules assemble at the gold support into several structures templated by the crystallography of the metal surface and involving flat or edge-on adsorbed molecules. Studies of the film formed by fusion of mixed DMPC/cholesterol vesicles revealed that ordered domains of either pure DMPC or pure cholesterol were formed. These results indicate that, at the metal surface, the molecules released by the rupture of a vesicle initially self-assemble into a well-ordered monolayer. The self-assembly is controlled by the hydrocarbon skeleton-metal surface interaction. In the case of mixed DMPC/cholesterol vesicles, the molecule-metal interactions induce segregation of the two components into single component domains. However, the molecule-metal interaction induced monolayer is a transient phenomenon. When more molecules accumulate at the surface, the molecule-molecule interactions dominate the assembly, and the monolayer is transformed into a bilayer.

A regio-specific synthesis of N-substituted imidazoles is described. Readily available α-amino acids are converted to α-aminocarbonyl derivatives and reacted with various isothiocyanates to give N-substituted cyclic thioureas. Oxidative or reductive desulfurization of the cyclic thioureas affords structurally diversified imidazoles in good to excellent yields.

A novel series of piperazines appended to a succinamide backbone were synthesized and found to have a high affinity for the melanocortin-4 receptor (IC(50)s ranging from

We described the first scanning tunneling microscopy study of spreading unilamellar vesicles of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) at a Au(111) electrode surface. At the initial stage of the film formation, the molecular resolution images revealed that DMPC molecules are adsorbed flat with the acyl chains oriented parallel to the surface. The molecules assemble into double rows by aligning the acyl chains in the nearest neighbor direction of the reconstructed Au(111) surface and assuming a 90 +/- 10 degrees angle with respect to line of the molecular row. After approximately 30 min, this film is transformed into a hemimicellar state with long rows characteristic for the formation of hemicylindrical surface micelles. At hydrophilic surfaces such as glass, spreading of vesicles involves adsorption, rupture, and sliding of a single bilayer on a lubricating film of the solvent. We have provided the first evidence that a different mechanism is involved in spreading the vesicles at gold. The molecules released by rupture of vesicles self-assemble into an ordered film, and the assembly is controlled by the chain-substrate interaction.