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A type of styrene-butadiene-styrene (SBS) and crumb rubber (CR) composite modified asphalt (CMA) binder with a chemical (-C) method was proposed in this research. Dynamic shear rheometer (DSR) tests were conducted at different frequency and temperature to evaluate rheological properties of SBS/CR-C CMA in different aging conditions. Rheological master curves were also constructed to survey its rheological properties in a broad range of frequencies and temperatures. Based on test results, it was concluded that the rheology of SBS/CR-C CMA prepared by ultra-fine embedding grafting technology has been improved over a wide temperature range, showing good high and low temperature properties. In the low temperature domain, the asphalt provides good fatigue resistance attributed to the elastic property of CR. And in the high temperature domain, the copolymer network significantly improves the elastic response of SBS/CR-C CMA, showing better deformation recovery. In addition, short- and long-term aging enhance the shear deformation resistance and elastic behavior of SBS/CR-C CMA, but weaken the low-temperature cracking and fatigue resistance performance. SBS/CR-C CMA has excellent anti-aging property.

The paper investigated the low temperature performance of asphalt binders modified by SBS, SBS/crumb rubber (CR) and SBS/TAFPACK-Super (TPS). The bending beam rheometer (BBR) test was utilized to compare the rheological properties of three modified asphalt binders at low temperatures. Firstly, the low service temperature of three asphalt binders was calculated from the BBR test results according to the Performance Grading (PG) protocol. Secondly, the generalized fractional viscoelastic model was introduced to construct the master curve of the flexural creep stiffness based on the time-temperature superposition principle. Then the property of three asphalt binders at low temperatures was compared by three approaches based on the generalized fractional model, including the graph of master curve, the derivation of creep compliance and dissipated energy ratio. The comparison results of different indicators showed that the SBS/CR compound modified asphalt had the best low temperature performance followed by the SBS/TPS asphalt and SBS asphalt. Additionally, the strain energy density of three-point bending test and the fracture temperature of thermal stress restrained specimen test (TSRST) for asphalt mixtures further proved the superiority of low temperature crack resistance of SBS/CR compound modified asphalt mixtures. Finally, the results of grey rational analysis demonstrated that the dissipated energy ratio of asphalt binders had a good correlation with the low temperature performance of asphalt mixtures. The study indicates that the SBS/CR compound modified asphalt binder could better meet the demands of pavement materials in cold regions.

SAR in the previously described spirocyclic ROMK inhibitor series was further evolved from lead 4 by modification of the spirocyclic core and identification of novel right-side pharmacophores. In this process, it was discovered that the spiropyrrolidinone core with the carbonyl group α to the spirocenter was preferred for potent ROMK activity. Efforts aimed at decreasing hERG affinity within the series led to the discovery of multiple novel right-hand pharmacophores including 3-methoxythiadiazole, 2-methoxypyrimidine, and pyridazinone. The most promising candidate is pyridazinone analog 32 that showed an improved functional hERG/ROMK potency ratio and preclinical PK profile. In vivo evaluation of 32 demonstrated blood pressure lowering effects in the spontaneously hypertensive rat model.

Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic β-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.

The application of asphalt concrete waterproofing layer (ACWL) for the subgrade has been a trend in Chinese high-speed railway. The purpose of this research is to discuss the dynamic characteristics of full cross-section ACWL in the ballastless track structure under the train loads. The laboratory tests were conducted to evaluate the performance of the asphalt mixtures for the ACWL and a test section of ACWL was constructed on the high-speed railway in north China. The linear viscoelastic behavior of the asphalt concrete obtained from the test section was characterized by the generalized Maxwell model according to the results of dynamic modulus test. Then a 3D finite element model for the interaction system of vehicle and ballastless track structure was presented and validated by field measured data. The results indicated that the tensile strain at the bottom of the ACWL was at a relatively low level and the vertical dynamic responses of each structural layer are obviously reduced due to the application of ACWL. Therefore, the full cross-section ACWL helps to reduce the vibration of the track structure and maintain the long-term stability of the subgrade.

In urban construction, more and more foundation pit excavations are adjacent to existing buildings with composite foundations. Therefore, it is necessary to study the interaction between foundation piles and supporting structures. In this article, a centrifuge model test has been carried out to study the vertical load transfer behavior of composite foundation with rigid piles and its responses to adjacent excavation. The test model was designed based on a real excavation project adjacent to an existing composite foundation. The sand pluviation method was used to build the foundation model. An in-flight excavation method and a loading device for multilevel uniform surface load were used in the test. Finally, the variations of induced axial force, pile skin friction, and pile-soil stress ratio along with the depth were investigated. Some useful conclusions can be drawn as follows: (1) the negative skin friction in the upper part of piles, induced by the overlaying load, increases first and then decreases along with the depth; (2) pile-soil stress ratio decreases along with the depth under initial loads, while it increases first and then decreases when the load is larger; (3) pile-soil stress ratio always increases with loads in the same depth, indicating that mobilized skin friction of piles is continuously developed; and (4) more significant changes of the axial force, skin friction, and pile-soil stress ratio of composite foundation piles are observed in the shallow soil and for the later excavation stage. Therefore, the deformation of the foundation pit should be strictly controlled during the later excavation stages.

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic β-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6 . GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10 mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.

During nearly a decade of research dedicated to the study of sphingosine signaling pathways, we identified sphingosine-1-phosphate lyase (S1PL) as a drug target for the treatment of autoimmune disorders. S1PL catalyzes the irreversible decomposition of sphingosine-1-phosphate (S1P) by a retro-aldol fragmentation that yields hexadecanaldehyde and phosphoethanolamine. Genetic models demonstrated that mice expressing reduced S1PL activity had decreased numbers of circulating lymphocytes due to altered lymphocyte trafficking, which prevented disease development in multiple models of autoimmune disease. Mechanistic studies of lymphoid tissue following oral administration of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI) 3 showed a clear relationship between reduced lyase activity, elevated S1P levels, and lower levels of circulating lymphocytes. Our internal medicinal chemistry efforts discovered potent analogues of 3 bearing heterocycles as chemical equivalents of the pendant carbonyl present in the parent structure. Reduction of S1PL activity by oral administration of these analogues recapitulated the phenotype of mice with genetically reduced S1PL expression.

The 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold (I) embodies a motif that allows it to dock to the active site of (chymo)trypsin-like proteases in a predictable and substrate-like fashion. Consequently, inhibitors derived from this heterocyclic scaffold interact with both the S and S′ subsites of an enzyme. Exploitation of binding interactions with both the S and S′ subsites of a target enzyme may lead to compounds with greatly enhanced enzyme selectivity and inhibitory potency. This preliminary report describes the use of a series of compounds having the heterocyclic scaffold linked to various amino acids to probe the S′ subsites of human leukocyte elastase (HLE), proteinase 3 (PR 3), and cathepsin G (Cat G). For comparative purposes, a series of compounds derived from a related scaffold, isothiazolidin-3-one 1,1 dioxide (II), was also generated. Several of the compounds were found to be highly potent and selective time-dependent inhibitors of HLE, PR 3, and Cat G.

A convenient single step methodology for the N-chloromethylation of heterocyclic imides using a mixture of formaldehyde sodium bisulfite adduct and thionyl chloride is described.

The lamellar liquid crystalline phase in the system consisting of sodium oleate (NaOL), oleic acid (OLA), and water was determined. The interlayer spacing (d) of the lamellar liquid crystal was measured through small angle X-ray diffraction, which indicated that oleic acid molecules were solubilized between the end methyl groups at low concentrations, and then were located within the hydrocarbon chain layer with further increase of its concentration. Cross-linking agents were added to the system, which were found being located partly in between the end methyl groups and partly within the hydrocarbon chain layers. The liquid crystal phase of NaOL/OLA/H2O system with the cross-linking agent was polymerized at 60 °C, which turned out to be a mixture of liquid crystals and solids. Interlayer spacing decreased by about 10 A, indicating a disruption of the ordered structure by the polymerization. The polymerization took place not only within the hydrocarbon layer, but also in between the layers separat...

A convenient single step methodology for the N-chloromethylation of heterocyclic imides using a mixture of formaldehyde sodium bisulfite adduct and thionyl chloride is described.

A series of potent piperidine-linked cytosine derivatives were prepared as inhibitors of deoxycytidine kinase (dCK). Compound 9h was discovered to be a potent inhibitor of dCK and shows a good combination of cellular potency and pharmacokinetic parameters. Compound 9h blocks the incorporation of radiolabeled cytosine into mouse T-cells in vitro, as well as in vivo in mice following a T-cell challenge.

A series of deoxycytidine kinase inhibitors was simultaneously optimized for potency and PK properties. A co-crystal structure then allowed merging this series with a high throughput screening hit to afford a highly potent, selective and orally bioavailable inhibitor, compound 10. This compound showed dose dependent inhibition of deoxycytidine kinase in vivo.

The lamellar liquid crystalline (LLC) regions of sodium oleate (NaOL)/ water/hexadecane/4-allyl-1,6-heptadiene-4-ol (AHD-ol) system and sodium oleate (NaOL) /water/hexadecane/pentaerythritol triacrylate (PETA) system were determined when the weight ratio of NaOL to hexadecane was kept at 90:10. Copolymerization was accomplished in the LLC phases of the above systems. AHD-ol and PETA acted as the cross-linking agents between the double bonds on NaOL backbones in their systems respectively. Interlayer spacing determinations showed that the cross-linking agents, AHD-ol and PETA, were solubilized in the middle of the NaOL hydrocarbon chains in each LLC system. As a result, the copolymerization reactions were confined within each monolayer of the amphiphilic bilayer. The systems after the copolymerization were a mixture of water and LLC phase for the former system and a mixture of LLC phase and solid particles for the latter one. The aqueous solutions of copolymers exhibited surface activity, but with both higher CMC and surface tension values than NaOL aqueous solutions.