4‐Benzothiazole‐7‐hydroxyindolinyl Diaryl Ureas Are Potent P2Y1 Antagonists with Favorable Pharmacokinetics: Low Clearance and Small Volume of Distribution

Current antithrombotic discovery efforts target compounds that are highly efficacious in thrombus reduction with less bleeding liability than the standard of care. Preclinical data suggest that P2Y₁ antagonists may have lower bleeding liabilities than P2Y₁₂ antagonists while providing similar antithrombotic efficacy. This article describes our continuous SAR efforts in a series of 7‐hydroxyindolinyl diaryl ureas. When dosed orally, 4‐trifluoromethyl‐7‐hydroxy‐3,3‐dimethylindolinyl analogue 4 was highly efficacious in a model of arterial thrombosis in rats with limited bleeding. The chemically labile CF₃ group in 4 was then transformed to various groups via a novel one‐step synthesis, yielding a series of potent P2Y₁ antagonists. Among them, the 4‐benzothiazole‐substituted indolines had desirable PK properties in rats, specifically, low clearance and small volume of distribution. In addition, compound 40 had high i.v. exposure and modest bioavailability, giving it the best overall profile.     

Behavioral observations and measurements of aerial pheromone in a mating disruption trial against pea mothCydia nigricana F. (Lepidoptera,Tortricidae)

Synthetic sex pheromone of the pea mothCydia nigricana. (E,E)-8,10-dodecadien-1-yl acetate (E8,E10–12 : Ac), was applied in a 3-ha pea field at a rate of 17 g/ha, in two different dispenser formulations. Aerial concentrations within pea canopy, as determined by a field electroantennogram (EAG) apparatus, were 2 and 3 ng/m³ in the two dispenser treatments. The validity of the EAG measurements was corroborated by sampling of field air, followed by gas chromatographic quantification ofE8,E10–12 : Ac. Males were attracted to fresh dispensers releasingE8,E10–12 : Ac plus less than 2% of the antagonisticE, Z; Z, E; andZ, Z isomers. Two days after placement, the proportion of these isomers had increased to 6%. Males were then no longer attracted to the dispensers, but were observed to fly out of the treated field. Male attraction to calling females was almost entirely suppressed, and attraction to traps baited with synthetic pheromone was significantly reduced. Larval infestation in the pheromone-treated field was 2%, compared to 36% in a control field.     

Studies on Plant Calmodulin and Its Interaction with Antagonist W7 by Ln3+ Luminescence Probes

ＳｔｕｄｉｅｓｏｎＰｌａｎｔＣａｌｍｏｄｕｌｉｎａｎｄＩｔｓＩｎｔｅｒａｃｔｉｏｎｗｉｔｈＡｎｔａｇｏｎｉｓｔＷ７ｂｙＬｎ３＋ＬｕｍｉｎｅｓｃｅｎｃｅＰｒｏｂｅｓＬｉｕＤｅｌｏｎｇ（刘德龙），ＹａｎｇＹａｎｓｈｅｎｇ（杨燕生）（Ｄｅｐａｒｔｍｅ...     

Alpha(1) adrenoceptor subtype selectivity. 3D-QSAR models for a new class of alpha(1) adrenoceptor antagonists derived from the novel antipsychotic sertindole

Receptor-binding affinities for the alpha(1) adrenoceptor subtypes alpha(1a), alpha(1b) and alpha(1d) for a series of 39 alpha(1) adrenoceptor antagonists derived from the antipsychotic sertindole are reported. The SAR of the compounds with respect to affinity for the alpha(1a), alpha(1b) and alpha(1d) adrenoceptor subtypes as well as affinity obtained by an alpha(1) assay (rat brain membranes) were investigated using a 3D-QSAR approach based on the GRID/GOLPE methodology. Good statistics (r(2)=0.91-0.96; q(2)=0.65-0.73) were obtained with the combination of the water (OH2) and methyl (C3) probes. The combination of steric repulsion and electrostatic attractions explain the affinities of the included molecules. The adrenergic alpha(1a) receptor seems to be more tolerant to large substituents in the area between the indole 5- and 6-positions compared to the adrenergic alpha(1b) and alpha(1d) receptor subtypes. There seems to be minor differences in the position of areas in the alpha(1b) receptor compared to alpha(1a) and alpha(1d) receptors where electrostatic interaction between the molecules and the receptor (OH2 probe) contribute to increased affinity. These observations may be used in the design of new subtype selective compounds. In addition, the model based on biological data from an alpha(1) assay (rat brain membranes) resembles the model for the alpha(1b) adrenoceptor subtype.     

Compound interactions effects of plant antioxidants in combination with carbaryl on performance ofTrichoplusia ni (Cabbage Looper)

Plant chemicals naturally exist in complex mixtures, which can interact either additively, synergistically, or antagonistically. We investigated the potential interactions of three naturally occurring antioxidants— nordihydroguaiaretic acid (NDGA), safrole, and -tocopherol—with the general insecticide carbarayl to affect the performance of cabbage looper larvae (Trichoplusia ni). The cabbage looper is known to produce a mixed-function oxidase enzyme system in response to the presence of carbaryl. We proposed that plant antioxidants would interfere with enzymatic oxidation, enhancing the susceptibility of this insect to carbaryl. Insects were fed artificial diets containing each antioxidant alone or in pairwise combinations with the insecticide carbaryl to test for their effects on the insect's nutritional measurement indices. The three antioxidants tested were not equally effective individually against insect survivorship and interacted differentially in combination with the insecticide. The nutritional indices were measured on insects fed diets containing the chemicals at nonlethal doses. Insects fed 0.001 % wet wt NDGA diets grew 1.62 times less, and had gross and net conversion efficiencies reduced 3.20 and 3.63 times, respectively, compared to the control larvae. Carbaryl (0.002% wet wt) in combination with NDGA acts as an antagonist to the effects mentioned above, while safrole (1 × 10^–4 wet wt) had an additive effect when combined with the insecticide, reducing 1.76 times larval relative growth rate and efficiency of conversion of ingested food in respect to the control. The larvae fed significantly more (1.2 times) on both insecticide and safrole diets than on the controls or their combined diets. Larvae fed -tocopherol alone or in combination with carbaryl had similar growth and conversion efficiencies as controls. We conclude that the effects of different combinations of compounds cannot be predicted a priori and must be determined experimentally.Operated for the U.S. Department of Energy by the University of California under Contract No. DE-ACO3-76-SF00012. This article was supported by the Center for Intermedia Transport Research (EPA Contract CR-81172-01) and by the Ecological Research Division of the Office of Health and Environmental Research, U.S. Department of Energy.     

沃拉帕沙中间体手性氨基环己烯基丙烯酸的合成工艺改进

摘要：以(E)-3-(5-硝基-1-环己烯基)丙烯酸(Ⅱ)为原料,经酯化、硝基还原、拆分、缩合、水解等反应制备了(R,E)-3-(5-乙氧羰基氨基-1-环己烯基)丙烯酸(Ⅰ)。就Ⅰ合成的各歩反应条件进行了优化。其中,(R,E)-3-(5-氨基-1-环己烯基)丙烯酸乙酯的制备采用D-苹果酸作为拆分剂,甲醇:丙酮=1:1作为溶剂,收率为35.6%。改进后目标产物的总收率达到了27.4%。新合成路线操作简便,反应条件温和,使用的原料和试剂成本都比较低廉,适合工业化生产。目标化合物及中间体的结构经1HNMR、ESI-MS等确证。     

Dynamic modeling of an anthropomimetic robot in contact tasks

Considerations of energy efficiency and safe human-robot interaction have led to an increase in the exploitation of compliance in robotics, and much of this work has been inspired by biological systems. As a consequence, new analytical tools are now required in order to enable the dynamic analysis of these novel compliant robots, especially in their interactions with the environment. This paper extends the ‘Flier’ approach to show how it could be applied to the dynamic analysis of contact tasks involving a highly compliant biologically inspired robot – in this case an anthropomimetic robot, a humanoid with a human-like skeleton and artificial muscles, in which the joints are actuated by DC motors acting via compliant tendon transmissions. First, a computer-based model of the robot’s dynamics is developed. Various constraints are then introduced to describe the contacts (including impacts) with the ground, and with objects in the environment. Simulation results are presented for two types of interactions with the external world: a grasping task and the case of the robot moving on a mobile base.     

Neuromechanical control for hexapedal robot walking on challenging surfaces and surface classification

The neuromechanical control principles of animal locomotion provide good insights for the development of bio-inspired legged robots for walking on challenging surfaces. Based on such principles, we developed a neuromechanical controller consisting of a modular neural network (MNN) and of virtual agonist–antagonist muscle mechanisms (VAAMs). The controller allows for variable compliant leg motions of a hexapod robot, thereby leading to energy-efficient walking on different surfaces. Without any passive mechanisms or torque and position feedback at each joint, the variable compliant leg motions are achieved by only changing the stiffness parameters of the VAAMs. In addition, six surfaces can be also classified by observing the motor signals generated by the controller. The performance of the controller is tested on a physical hexapod robot. Experimental results show that it can effectively walk on six different surfaces with the specific resistances between 9.1 and 25.0, and also classify them with high accuracy.     

Structure-function analysis of human IL-1{alpha}: identification of residues required for binding to the human type I IL-1 receptor

Using oligonucleotide-directed mutagenesis, the binding siteon human interleukin-1 (IL-1) for the human type I IL-1 receptor(IL-1R) has been analyzed. Substitution of seven amino acids(Arg12, Ile14, Asp60, Asp61, Ile64, Lys96 and Trp109) resultedin a significant loss of binding to the receptor. Based on crystallographicinformation, the side chains of these residues are clusteredin one region of IL-1 and exposed on the surface of the protein.Five of the residues in the IL-1 binding site align with thebinding residues previously determined in human IL-1ß,demonstrating that the type I IL-1R recognizes homologous regionsin both ligands. Unexpectedly, only three of the aligned residuesare identical between IL-1 and IL-1ß. These observationssuggest that the composition of contact residues in the bindingsite is unique for each ligand–receptor complex in theIL-1 system.     

Sex Pheromone of the Dogwood Borer, <Emphasis Type="Italic">Synanthedon scitula</Emphasis>

The sex pheromone of female dogwood borers (DWB) Synanthedon scitula (Harris) (Lepidoptera: Sesiidae) was determined to be an 88:6:6 ternary blend of (Z,Z)-3,13-octadecadienyl acetate (Z,Z-3,13-ODDA), (E,Z)-2,13-octadecadienyl acetate (E,Z-2,13-ODDA), and (Z,E)-3,13-octadecadienyl acetate (Z,E-3,13-ODDA) by gas chromatography–electroantennographic detection (GC–EAD) and gas chromatography–mass spectrometry (GC–MS). The major sex pheromone component, Z,Z-3,13-ODDA, was attractive as a single component. A blend of Z,Z-3,13-ODDA with 1–3% of E,Z-2,13-ODDA (binary blend) was more attractive than the single component. A third component, Z,E-3,13-ODDA, was sometimes observed in GC–EAD analyses, and enhanced attraction to the binary blend in some field bioassays. Lures containing 1 mg of binary and ternary blends attracted 18 and 28 times more male DWB moths, respectively, than caged virgin females in field trials. Attraction was strongly antagonized by addition of as little as 0.5% of E,Z-3,13-octadecadienyl acetate (E,Z-3,13-ODDA). In a period of 12 wk in 2004, more than 60,000 males were captured in sticky traps baited with synthetic pheromone blends in six apple orchards in Virginia, West Virginia, and North Carolina. Lure longevity trials showed that ∼76% of the pheromone remained in rubber septum lures after 12 wk in the field.