Preparation and Diels-Alder reactions of 1'-heterosubsituted vinylimidazoles.

A Diels-Alder/rearrangement sequence has been pursued in our lab en route to a number of oroidin dimers. In order to access the fully substituted core of these molecules, 1',2'-disubstituted 4-vinylimidazoles were required as dienes. The preparation of a series of a 4-vinylimidazoles containing substituents on the vinyl moiety via hydroalumination/electrophilic trapping or hydrosilylation are described. These derivatives undergo Diels-Alder reactions with N-phenylmaleimide to provide the tetrahydrobenzimidazole derivatives. The cycloadducts derived from halosubstituted systems generally undergo elimination, leading to the corresponding dihydrobenzimidazole, whereas the silyl and stannyl derivatives provide the corresponding 4-substituted tetrahydrobenzimidazole.

Physical modeling and geometric shape simulation for one-dimensional flexible objects with cylindrical surface constraints.

This study develops forces equilibrium differential equations for the geometric modeling of 1D flexible objects with surface constraints. These second-order equations are an extension of the Cosserat elastic rod theory and include both bending and torsion. Variables were established for the centerline and attitude in the Cartesian coordinate system of the cross section. This paper specifically investigates the case of a 1D flexible object constrained by a cylindrical surface. To solve this problem, a novel hybrid semi-analytical numerical method is proposed. In this process, a Hamiltonian function and an initial integral operator are introduced in a cylindrical coordinate system. The analytical solution, decoupled in polar coordinates, is then derived. The improved finite difference method was then used to obtain three cylindrical coordinates, which ensured numerical stability and efficiency. The results of a geometric shape simulation with differing boundary conditions demonstrate that this proposed method is capable of real-time modeling. As such, this technique could be a promising new tool for use in graphics simulations of elongated structures, such as DNA molecules, drill pipes, and submarine cables.

The design, synthesis, and biological evaluation of PIM kinase inhibitors.

A series of substituted benzofuropyrimidinones with pan-PIM activities and excellent selectivity against a panel of diverse kinases is described. Initial exploration identified aryl benzofuropyrimidinones that were potent, but had cell permeability limitation. Using X-ray crystal structures of the bound PIM-1 complexes with 3, 5m, and 6d, we were able to guide the SAR and identify the alkyl benzofuropyrimidinone (6l) with good PIM potencies, permeability, and oral exposure.

Discovery of XL413, a potent and selective CDC7 inhibitor.

CDC7 is a serine/threonine kinase that has been shown to be required for the initiation and maintenance of DNA replication. Up-regulation of CDC7 is detected in multiple tumor cell lines, with inhibition of CDC7 resulting in cell cycle arrest. In this paper, we disclose the discovery of a potent and selective CDC7 inhibitor, XL413 (14), which was advanced into Phase 1 clinical trials. Starting from advanced lead 3, described in a preceding communication, we optimized the CDC7 potency and selectivity to demonstrate in vitro CDC7 dependent cell cycle arrest and in vivo tumor growth inhibition in a Colo-205 xenograft model.

SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors.

We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.

AG600 Amphibious Aircraft Selection Model Based on Improved Fuzzy Evaluation Algorithm.

Aiming at the selection research gap of AG600 amphibious aircraft for salvage of life at sea, the selection index system of AG600 has been established, and an interval intuitionistic fuzzy selection decision model based on fuzzy entropy and score function is constructed. An evaluation index system with 8 indexes was determined based on the rules of the applicability, safety, and accessibility by questionnaire and statistical analysis. Different from the traditional method of determining the fuzzy number of each index solely by experts' scoring, this paper establishes a 5-grade fuzzy evaluation grade and index membership function, and the interval intuitionistic fuzzy number of the index is determined by combining subjective and objective methods. Fuzzy entropy and score function are used to calculate the weights of each index and AG600 selection score for different accidents, so as to obtain the matching degree of AG600 selection in marine life accidents more scientifically and reasonably. Finally, the effectiveness of the proposed model is demonstrated by a practical case.

Computer-aided optimal design for flexible cable in aerospace products based on dynamic analogy modeling.

Due to large, complex deformations, the accurate design of cables has become a major problem in the manufacturing of aerospace products. The current design method often leads to large products, uncertain centroids, and poor reliability. To solve these problems, a computer-aided optimal design method for flexible cables was proposed based on dynamic analogy modeling. A nonlinear optimization model was established by combining Cosserat theory and the minimum potential energy principle. The total deformation energy was considered as the optimization object, and Euler parameters were used as control variables to describe the cable geometric shape. Considering the length and bending radius requirements, the normalized form of the cable constraints was expressed by the cross-section position and orientation matrix. An efficient method to solve this problem using finite element discretization and the primitive dual interior point method was proposed. A digital wiring module was developed based on an open source geometry kernel system, and a cable geometry test bench was built. To verify our model, a satellite wiring simulation example was implemented using the module, SolidWorks, and the test bench. Our method achieved the optimal design for the cable length and geometric shape. A theoretical and technical foundation for effectively solving the problem of large cable manufacturing errors and realizing the lightweight design of aerospace products was outlined.

Discovery of a new class of glucosylceramide synthase inhibitors.

A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo.

Applicability of bridge-type pneumatic energy-saving systems and its experimental validation.

The bridge-type pneumatic system is to control the intake and exhaust time sequences of an air cylinder with four switch valves by applying the expansion energy of air for work to save energy. However, the system is often sensitive, and thus, the control accuracy can be rather poor. Therefore, the applicability of this system remains to be further tested. A nonlinear dynamic optimization model with the air consumption as the objective function was established. A simultaneous collocation method was used to obtain the on-off time sequences. The concept of optimization performance rating to evaluate the system's energy-saving performance and the stability was introduced. Experiments were done to validate the applicability of the circuit. The results showed that the bridge circuit was applicable to a certain range of working conditions under each given action system and that instability, such as rebound or impact, could occur outside this range.

Oxidative rearrangement of imidazoles with dimethyldioxirane.

Tetrahydrobenzimidazoles, on treatment with dimethyldioxirane, rearrange to provide 5-imidazolones exclusively. These rearrangements proceed with a broad range of substrates and with good to excellent levels of diastereoselectivity. [reaction: see text]

Discovery and characterization of an inhibitor of glucosylceramide synthase.

Targeting glycosphingolipid synthesis has emerged as a novel approach for treating metabolic diseases. 32 (EXEL-0346) represents a new class of glucosylceramide synthase (GCS) inhibitors. This report details the elaboration of hit 8 with the goal of achieving and maintaining maximum GCS inhibition in vivo. 32 inhibited GCS with an IC(50) of 2 nM and achieved maximum hepatic GCS inhibition after four or five daily doses in rodents. Robust improvements in glucose tolerance in DIO mice and ZDF rats were observed after 2 weeks of q.d. dosing. Four weeks of dosing resulted in decreased plasma triglycerides and reduced hepatic fat deposition. Thus, 32 provides insight into the amount of metabolic regulation that can be restored following achievement of maximal target knockdown.

Preparation and Diels-Alder chemistry of 4-vinylimidazoles.

Various 4-vinylimidazole derivatives have been prepared from the corresponding 4-iodoimidazoles or from urocanic acid. Several methods for the elaboration of these vinylimidazoles and their Diels-Alder reactions are reported. All of the vinylimidazoles prepared in the course of this study react with N-phenylmaleimide quite readily with mild thermal activation providing a single cycloadduct, in most cases the initial, nonaromatic adduct. With more electron rich substrates, there is a tendency for these initial cycloadducts to undergo aromatization, ene reaction, and oxidation although this can be circumvented to a large extent by the choice of reaction conditions. Limited reactions were observed with other dienophiles, providing the expected cycloadducts in most cases, although an abnormal adduct was obtained in one case with dimethyl acetylene dicarboxylate. These substrates also participate in regioselective Diels-Alder reactions with monoactivated dienophiles, but require fairly forcing conditions, thus only providing the aromatized cycloadducts in modest yields. An investigation of substituent effects at the 2-position of the imidazole moiety was undertaken, in which electron-donating and weakly electron-withdrawing substituents are tolerated. In addition, several substrates with terminally substituted vinyl moieties have been investigated.