Vibration rejection of phased array telescope systems via disturbance-propagation-characteristics-based feedforward control.

Vibration rejection is one of the key techniques to stabilize the line of sight (LOS) for phased array telescope systems. Conventionally, feedback control based on image sensors is mainly used to correct the tip/tilt errors caused by disturbances and to keep the LOS stable. However, it is restricted by the sampling rate and time delay of image sensors, leading to a limited closed-loop bandwidth. Disturbances in the middle and high frequencies are hard to suppress. In this paper, disturbance-propagation-characteristics-based feedforward control is proposed to overcome these problems. A theoretical imaging model of the phased array telescope is developed to analyze the LOS disruption caused by disturbance. In addition, to improve the disturbance suppression bandwidth and correction accuracy of the system, the disturbance propagation characteristics of the phased array telescope system are analyzed. Combined with the disturbance feedforward, targeted compensation is achieved for the sub-apertures. Finally, a comparative experiment is carried out based on the self-developed Fizeau phased array telescope system to verify the superiority of the proposed method.

Discovery of Potent, Dual-Inhibitors of Diacylglycerol Kinases Alpha and Zeta Guided by Phenotypic Optimization.

We describe a phenotypic screening and optimization strategy to discover compounds that block intracellular checkpoint signaling in T-cells. We identified dual DGKα and ζ inhibitors notwithstanding the modest similarity between α and ζ relative to other DGK isoforms. Optimized compounds produced cytokine release and T-cell proliferation consistent with DGK inhibition and potentiated an immune response in human and mouse T-cells. Additionally, lead inhibitor BMS-502 demonstrated dose-dependent immune stimulation in the mouse OT-1 model, setting the stage for a drug discovery program.

Demonstration of a Fizeau Directly-Imaging Sparse-Aperture Telescope with Pointing and Tracking Capabilities.

At present, the majority of sparse-aperture telescopes (SATs) are unable to observe moving targets. In this paper, we describe the construction of and present the results obtained using a Fizeau directly-imaging sparse-aperture telescope (FDISAT) that permits pointing and the tracking of moving targets. The telescope comprises three sub-apertures, each of which is equipped with a Risley prism system that permits a maximum tracking range of 5° and has independent boresight adjustment capability. On targets in various positions, experiments with pointing and tracking are conducted. The maximum root-mean-square error (RMSE) of pointing in the sub-apertures was found to be 8.22 arcsec. When considering a target moving at 0.01°/s for approximately 320 s, the maximum RMSE of tracking in the sub-apertures was found to be 4.23 arcsec. The images obtained from the focal plane detector exhibit clear interference fringes while tracking. The experimental results demonstrate that the system can effectively track moving targets, providing a method for SAT observation of moving targets.

Robust Risley prism control based on disturbance observer for system line-of-sight stabilization.

In this paper, a robust control based on disturbance observer is proposed to improve the tracking accuracy of the Risley prism system (RPS). Applying the flexible thin-wall ring mechanism in the RPS causes a series of tracking and pointing challenges. Disturbances such as friction, shaft deformation, and model perturbation significantly deteriorate the tracking and pointing accuracy of the RPS. Two different observer-based control methods are proposed to guarantee the tracking precision of the RPS. Moreover, the disturbance observation and compensation (DOC) performance of the proposed methods is analyzed and compared. Finally, simulation and experiment results indicate that the proposed control methods, especially the DOC-expanded state observer control mode, obtain the best performance for disturbance rejection in the RPS.

Disturbance compensation of a multiaperture imaging system based on a coupling rotating prism using an improved model compensation control.

In this paper, a cascade double-loop control (DLC) combined with modeling compensation methods is proposed to improve the tracking precision of the multiaperture imaging system (MAIS). The application of the flexible thin-wall ring mechanism in the coupling rotating prism (CRP) system causes a series of tracking and pointing challenges. Disturbances such as friction, shaft deformation, and model perturbation significantly deteriorate the tracking and pointing accuracy of the CRP. Two different modeling compensation methods that are interfaced with classical DLC are proposed to guarantee the tracking precision of the MAIS. Moreover, the disturbance observation and compensation performance of two different modeling compensation methods are analyzed and compared. Finally, simulation and experiment results indicate that the proposed control methods, especially model compensation based on speed close-loop control, obtain the best performance for disturbance rejection in the MAIS.

Piston error correction of sparse aperture systems using the metaheuristic stochastic parallel gradient descent algorithm.

The next generation of optical telescopes will provide high-resolution imaging of celestial objects by using the aperture synthesis technique. To preserve the quality of the image, fast corrections of the pistons among subapertures have to be applied, namely, the co-phasing of the array. The image-based co-phasing method via an optimization procedure has been newly developed. Despite simplicity and strong commonality, when dealing with large piston errors, this correction method is also faced with a problem in which the metric function easily falls into the local convergence, especially in the case of broadband imaging with many subapertures. In this study, an improved stochastic parallel gradient descent (SPGD) algorithm based on heuristic search is proposed for co-phasing, termed the metaheuristic SPGD algorithm. The heuristic research scheme assists the original SPGD algorithm in getting rid of local extrema. By iterations of this algorithm, the synthetic system can be co-phased without any additional instruments and operations. The effectiveness of the proposed algorithm is verified by means of simulation. Given the efficiency and superiority, it is expected that the method proposed in this study may find wide applications in multi-aperture imaging.

Identification and Preclinical Evaluation of the Bicyclic Pyrimidine γ-Secretase Modulator BMS-932481.

A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce the bicyclic pyrimidine γ-secretase modulator BMS-932481. The compound showed robust reductions of Aß1-42 and Aß1-40 in the plasma, brain, and cerebrospinal fluid of mice and rats. Consistent with the γ-secretase modulator mechanism, increases in Aß1-37 and Aß1-38 were observed, with no change in the total amount of Aß1-x produced. No Notch-based toxicity was observed, and the overall preclinical profile of BMS-932481 supported its further evaluation in human clinical trials.

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder.

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (Ki = 4.0 nM) and selective inhibition of GluN2B receptor function (IC50 = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

Development of New Benzenesulfonamides As Potent and Selective Nav1.7 Inhibitors for the Treatment of Pain.

By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Nav1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.

Discovery of S3-Truncated, C-6 Heteroaryl Substituted Aminothiazine ß-Site APP Cleaving Enzyme-1 (BACE1) Inhibitors.

Truncation of the S3 substituent of the biaryl aminothiazine 2, a potent BACE1 inhibitor, led to a low molecular weight aminothiazine 5 with moderate activity. Despite its moderate activity, compound 5 demonstrated significant brain Aß reduction in rodents. The metabolic instability of 5 was overcome by the replacement of the 6-dimethylisoxazole, a metabolic soft spot, with a pyrimidine ring. Thus, truncation of the S3 substituent represents a viable approach to the discovery of orally bioavailable, brain-penetrant BACE1 inhibitors.

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aß Reduction in Rodents.

By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC50 < 1 nM). This compound demonstrated robust brain Aß reduction in rat dose-response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.

Design and optimization of tricyclic gamma-secretase modulators.

Beginning with a diaminotriazine screening hit, several series of novel, tricyclic gamma-secretase modulators (GSMs) were designed. The SAR of several related series of GSMs is presented, and the in vivo profile of a lead molecule from the series is described.

Synthetic aperture imaging by using spatial modulation diversity technology with stochastic parallel gradient descent algorithm.

In this paper, we propose and demonstrate the synthetic aperture imaging by using spatial modulation diversity technology with stochastic parallel gradient descent (SPGD) algorithm. Instead of creating diversity images by means of focus adjustments, the technology, proposed in this paper, creates diversity images by modulating the transmittance of individual sub-aperture of multi-aperture system, respectively. Specifically, spatial modulation is realized by switching off the transmittance of each sub-aperture with electrical shutters, alternately. Based on these multi diversity images, SPGD algorithm is used for adaptively optimizing the coefficients of Zernike polynomials to reconstruct the real phase distortions of multi-aperture system and to restore the near-diffraction-limited image of object. Numerical simulation and experimental results show that this technology can be used for joint estimation of both pupil aberrations and an high resolution image of the object, successfully. The technology proposed in this paper can have wide applications in segmented and multi-aperture imaging systems.

Identification and Preclinical Pharmacology of the γ-Secretase Modulator BMS-869780.

Alzheimer's disease is the most prevalent cause of dementia and is associated with accumulation of amyloid-ß peptide (Aß), particularly the 42-amino acid Aß1-42, in the brain. Aß1-42 levels can be decreased by γ-secretase modulators (GSM), which are small molecules that modulate γ-secretase, an enzyme essential for Aß production. BMS-869780 is a potent GSM that decreased Aß1-42 and Aß1-40 and increased Aß1-37 and Aß1-38, without inhibiting overall levels of Aß peptides or other APP processing intermediates. BMS-869780 also did not inhibit Notch processing by γ-secretase and lowered brain Aß1-42 without evidence of Notch-related side effects in rats. Human pharmacokinetic (PK) parameters were predicted through allometric scaling of PK in rat, dog, and monkey and were combined with the rat pharmacodynamic (PD) parameters to predict the relationship between BMS-869780 dose, exposure and Aß1-42 levels in human. Off-target and safety margins were then based on comparisons to the predicted exposure required for robust Aß1-42 lowering. Because of insufficient safety predictions and the relatively high predicted human daily dose of 700 mg, further evaluation of BMS-869780 as a potential clinical candidate was discontinued. Nevertheless, BMS-869780 demonstrates the potential of the GSM approach for robust lowering of brain Aß1-42 without Notch-related side effects.

Synthesis and in vivo evaluation of cyclic diaminopropane BACE-1 inhibitors.

The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.

Monosubstituted γ-lactam and conformationally constrained 1,3-diaminopropan-2-ol transition-state isostere inhibitors of ß-secretase (BACE).

The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.

Design and synthesis of benzoazepinone-derived cyclic malonamides and aminoamides as potent gamma-secretase inhibitors.

We report the synthesis of benzoazepine-derived cyclic malonamides (2) and aminoamides (3) as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. The in vitro structure-activity relationships of 2 and 3 along with dog pharmacokinetic results are described.