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We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.

An efficient and scalable synthesis of an antidiabetic drug, tofogliflozin (1), which was identified as a highly selective sodium glucose cotransporter 2 (SGLT2) inhibitor, is described. A key factor in the synthesis of 1 was the selection of the purpose-designed protecting group, which plays a strategic role in protection, chemoselective activation, and crystalline purification. The developed and optimized method made it possible to prepare 1 on a multidecagram scale without any column chromatography.

Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH5137291 is expected to offer a novel therapeutic approach against major types of castration-resistant prostate cancers.

Short-step and scalable transformations from 2,6-dibromopyridine to 6-bromopyridine-2-sulfonamide by means of halogen―metal exchange and subsequent reaction with sulfuryl chloride followed by amidation are established. Application of the method for the synthesis of various pyridine sulfonamides is also described.

A series of 5,5-dimethylthiohydantoin derivatives were synthesized and evaluated for androgen receptor pure antagonistic activities for the treatment of castration-resistant prostate cancer. Since CH4933468, which we reported previously, had a problem with agonist metabolites, novel thiohydantoin derivatives were identified by applying two strategies. One was the replacement of the alkylsulfonamide moiety by a phenylsulfonamide to avoid the production of agonist metabolites. The other was the replacement of the phenyl ring with a pyridine ring to improve in vivo potency and reduce hERG affinity. Pharmacological assays indicated that CH5137291 (17b) was a potent AR pure antagonist which did not produce the agonist metabolite. Moreover, CH5137291 completely inhibited in vivo tumor growth of LNCaP-BC2, a castration-resistant prostate cancer model.

We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like synoviocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis.

This paper reports on a gymnastic robot, which are developed for various floor exercises such as jumping, somersault and back handspring. The robot is a planar and serially connected four-link robot, whose joints are fully actuated by electric servomotors. In this paper, the modeling and the controller for back handspring are addressed. The controller is derived from task-specific target dynamics and its model matching. The use of global physical quantities such as center of mass, or angular momentum allows even simple target dynamics to generate complex gymnastic motions of multi-body system. The effectiveness of the controller is confirmed via simulations and experiments.

There are many robots which are controlled with PCs (Personal Computers) . Their typical OS (Operating System) was MS-DOS, but MS-DOS is not suitable for high level control. Therefore, RTLinux was developed as realtime OS. However, the authors tried to control mechatronic system by using common Linux and found that it has enough ability to control robots. In this paper, it is described why the common Linux can be used as OS for PCs that control robots. Some experimental results that indicate performance of common Linux as robot controlling OS are also provided. Then the control system developed for human type biped robot as an example that utilize this method is shown.

There are several types of motion capture system for virtual reality. The authors propose a new type of motion capture system that uses rotating magnetic field for angular position detection and differential magnetic field for linear position detection. The detection is based on calculation of correlation that makes accuracy of measurement and tolerance to noise high enough, and it is also based on frequency multiplex method that enables 6-axis measurement simultaneously. The experiments were carried out and results showed efficiently good performance for virtual reality.

The authors attempted to apply traction drive to a constant-speed servomechanism for Numerically Controlled (NC) machines. High-precision servomechanisms require high-resolution encoders to detect rotary position, whereas conventional high-resolution encoders cannot rotate at high speed. Therefore, the authors attempted to solve the problem of resolution and maximum rotary speed using a nonsinusoidal-wave quadrature Phase-Locked Loop (PLL). Using this nonsinusoidal-wave quadrature PLL for interpolating the tracking error, a very high-resolution detection of rotary angle at high-speed rotation was achieved even when using inexpensive encoders whose output is nonsinusoidal wave. Traction drive damps the high-frequency torque ripple, but transmits torque ripple of low frequency. Most of the torque ripple of low frequency is due to the eccentricity of rollers. As the rotary speed of rollers becomes high, the torque ripple has a frequency at which it cannot be eliminated either by traction drive or feedback control. Because the mechanism of torque ripple is very complicated, it is difficult to compensate by detecting roller eccentricity. Therefore, the authors used repetitive control to reduce the position error associated with roller rotation, and obtained high-accuracy rotation in the experiments. In this paper, the interpolation method of tracking error using a nonsinusoidal-wave quadrature PLL and the reduction method of tracking error using repetitive control are presented.

This paper describes a synchronous controller for high-productivity NC gear grinding machines that use a screw-shaped CBN wheel of multithread. The authors developed a high-precision controller for productive-type NC gear grinding machines in 1995. Because it was based on analog circuits, it required very complex electrical circuits. In this paper, we propose a PC-based synchronous controller to decrease production costs and add useful functions to it. The most useful one added this time is a function to increase pitch accuracy of gear ground with the multithread CBN wheel. Next useful one is a function to attain high-accuracy initial meshing between gear and CBN wheel. Because grinding-spindle and work spindle rotate at a high-speed, two-phase type PLL is applied to the controller. Grinding experiments showed that the newly developed controller has excellent performance.

This paper introduces some results of grinding test for decreasing grinding time in gear grinding. A prototype developed by the authors and an electroplated CBN worm of double threads were used for the test. To know whether high speed grinding impairs gear accuracy or not, some grinding experiments were carried out with changing rotary speed of a grinding spindle. And to know whether grinding with deep radial feed and rapid axial feed impairs gear accuracy or not, some experiments were also carried out with changing above conditions. In this case, the gears were ground into the root of the gear tooth for evaluating a performance of a servo controller of the prototype under heavy load. After experiments, it was confirmed that profile errors and pitch errors of the gears ground are very small at 7000 min-1 within a rated torque of the wheel spindle because angular positioning errors of grinding' spindle and workspindle of the prototype are always small enough. Moreover we examined a power consumption of the grinding spindle and cleared that it is in proportion to a removal stock rate of the gear tooth.

The authors tried to apply traction drive to a constant velocity servomechanism for NC machines. The 1st report described basic characteristics of the traction drive servomechanism. This 2nd report describes a method to achieve high-accuracy rotation. The high-precision servomechanism requires a high-resolution encoder to detect rotary position, whereas conventional high-resolution encoders can not rotate at high speed. Therefore, the authors tried to solve the problem of resolution and maximum rotary speed by using non-sinusoidal-wave two-phase type PLL (Phase Locked Loop). By using this non-sinusoidal-wave two-phase type PLL for interpolating tracking error, a very high resolution detection of rotary angle at a high speed rotation was achieved even using low-cost encoders of which output is non-sinusoidal wave. Traction drive damps torque ripple of high frequency, but transmits torque ripple of low frequency. Most part of torque ripple of low frequency is due to eccentricity of toilers. As the rotary speed of rollers gets high, the torque ripple has a frequency at which it can be eliminated neither by traction drive nor by feedback control. Because the mechanism of torque ripple is very complicated, it is difficult to conpemsate by detecting of rollers' eccentricity. Therefore, the authors used repetitive control to reduce the position error associated with roller rotation, and obtained high-accuracy rotation in the experiments. This paper presents the interpolation method of tracking error using non-sinusoidal-wave two-phase type PLL and the reduction method of tracking error using repetitive control.

This paper describes a new playback method of wheeled mobile robot. In this method, a moving path is divided into straight line parts and curve parts. The curve parts were approximated by the Beazier curve for decreasing data volume, and the only control points of the Bezier curve are memorized in teaching path. The tracking errors can be detected by referring pre-recorded images, and they are corrected by adjusting the Bezier curve. Experiments in the outdoors showed that the proposed method has good repeatahility in playback phase.

Traction drive has many advantages over a gear mechanism. For example, its backlash is negligible and instantaneous variation of reduction ratio is very small at any rotary angle. These advantages are attractive for high-precision servomechanisms that rotate at constant speed, such as NC gear processing machines. However, there has been little research reported on this subject so far. Thus, we developed a constant-velocity servomechanism that uses traction drive as its reduction mechanism, and carried out experiments to confirm its performance. Moreover, we propose torque compensation using slip-speed feedback to compensate the effect of torque disturbance and confirmed its usefulness by experiments. In this paper, the dynamics of the traction drive applied to constant velocity servomechanisms is introduced, and the method of disturbance compensation using slip-speed feedback is discussed. Then, details of the traction drive, control system and detecting systems are described, and the experimental results are presented.

This paper deals with a trial of gear grinding using a vitrified-bonded CBN wheel of screw shape. Compared with an electroplated CBN wheel, a vitrified-bonded CBN wheel is more suitable for obtaining gears of high accuracy because it permits the profile to correct and refine the cutting edge without removing the wheel from a spindle head using an onmachine type truing device. Then the authors designed this truing device and carried out some grinding experiments using a metal-bonded diamond wheel of V-shape for a truing cutter, and proposed a dressing process using gear-shaped GC wheel after truing. This dressing process has an effect to reduce the grinding force without impairing gear accuracy. The grinding results showed small profile errors and pitch errors in case of grinding speed at 7 000 min-1 with double-threads wheel whose diameter was 200 mm, and it was confirmed that we can use a vitrified-bonded CBN wheel of screw shape for gear grinding.

A scalable one-pot transformation via halogen—metal exchange allows the preparation of various title compounds and analogues as important intermediates in drug synthesis.

A new servomechanism for high speed servo-spindle of NC gear grinding machines is presented in this paper. The NC gear grinding machine requires high speed servo-spindles with extremely high accuracy. However, it is not easy to keep the rotary accuracy high enough at a high speed rotation. Usually, the resolution of a rotary encoder decreases with the increase of rotational speed by reason of response-frequency, and it becomes extremely low at speeds of more than 1000 rpm. Since the rotary accuracy changes in proportion to the resolution, the authors used a magnetic scale of high accuracy and tried to raise the resolution by means of two-phase type PLL proposed by Emura. The servomotor driving the servo-spindle is an A.C. induction motor controlled by the vector control method, and its rated power is 7.5 kW. To increase the servo-stiffness of the spindle, an inertial damper was used. This damper is very effective and can increase the position-loop-gain stably and extremely. Two high speed servo-spindles of the same structure were used as a grinding spindle and a work spindle of a newly designed NC gear grinding machine, and some grinding experiments were carried out. As a result of these experiments, it became clear that the servo-spindle developed by the authors is very suitable for the NC gear grinding machines.

This paper describes a new steering mechanism proposed by one of the authors(T.E.). This steering mechanism using noncircular gears has the capability of turning a carrier with a small radius. In order to facilitate the analysis of the steering mechanism, the concept of a virtual two-wheeled vehicle was introduced. As a result of analysis made by the other author (A.A.), it was proven that the noncircular gear for the steering mechanism is an elliptical gear of which the pitch curve can be represented by a simple equation. In addition, a method to apply this mechanism to wheeled robots, such as the carrier robots used in industrial production lines, was studied. It was confirmed that the concept of the virtual two-wheeled vehicle is very useful in the design of the steering mechanism.

Hyaluronic acid (HA) provides synovial fluid viscoelasticity and has a lubricating effect. Injections of HA preparations into the knee joint are widely used as osteoarthritis therapy. The current HA products reduce pain but do not fully control inflammation. Oral methotrexate (MTX) has anti-inflammatory efficacy but is associated with severe adverse events. Based on the rationale that a conjugation of HA and MTX would combine the efficacy of the two clinically evaluated agents and avoid the risks of MTX alone, we designed HA-MTX conjugates in which the MTX connects with the HA through peptides susceptible to cleavage by lysosomal enzymes. Intra-articular injection of our HA-MTX conjugate (conjugate 4) produced a significant reduction of the knee swelling in antigen-induced arthritis rat, whereas free MTX, HA or a mixture of HA and MTX showed no or marginal effects on the model. The efficacy of conjugate 4 was almost the same as that of MTX oral treatment. Conjugate 4 has potential as a compound for the treatment of osteoarthritis.

An efficient method for asymmetric synthesis of the potent Gastrin/CCK-B receptor antagonist AG-041R was developed. Core oxindole stereochemistry was established by asymmetric alkylation of oxindole enolates with bromoacetic acid esters, using l-menthol as a chiral auxiliary. The key alkylation reaction of the oxindole enolates generated tetrasubstituted chiral intermediates with high diastereoselectivity. The stereoselective alkylation reactions are described in detail.

A series of 7α-substituted dihydrotestosterone derivatives were synthesized and evaluated for androgen receptor (AR) pure antagonistic activity. From reporter gene assay (RGA), the compound with a side chain containing N - n -butyl- N -methyl amide ( 19a ) showed pure antagonistic activity (IC 50 = 340 nM, FI 5 > 10,000 nM), whereas known AR antagonists showed partial agonistic activities. The optimization of 19a led to compound 23 ( CH4892280 ), which showed more potent pure antagonistic activity (IC 50 = 190 nM, FI 5 > 10,000 nM). The SARs of tested compounds suggested that the length of the side chain and the substituents on the amide nitrogen are important for pure antagonistic activities.

This paper describes a new trajectory measurement system for small mobile robots. Wheeled robots such as automatically guided vehicles generally use the dead reckoning method to move to a desired position. In order to improve on the dead reckoning method, a trajectory measurement device which can measure the positional and directional errors with high accuracy is required. The authors made a measurement system using a CCD camera which tracks the vehicle automatically. In this paper, after briefly describing the outline of this measurement system, a calibration method to reduce the measurement error in wide measurement area and a tracking method which enables the system to track the vehicle moving at high speed without losing its image are proposed. Some experiments to measure the actual path of a small vehicle were carried out and it was confirmed that the measurement system has enough capability of detecting the trajectory error.

This paper describes a trajectory generation method for wheeled mobile robot. When a vehicle autonomously moves in an unknown environment, the vehicle must make the motion planning in real time. If a rough guideline is given for the trajectory, the motion planning becomes easy relative to the situation without any landmarks. However, even in that case, the vehicle must generate a desired trajectory for itself from the information on the guideline, for example, the positional data of the guideline obtained by using a vision system mounted on the vehicle. The authors propose a new trajectory generation method using Bezier curves, which is suitable for real time processing and has the capability of smoothly reducing the deviation from the guideline. In this paper, the trajectory generation method is described in detail, then the effectiveness is confirmed by simulations and experiments using a wheeled mobile robot developed by the authors.

The authors developed a productive type NC (numerically controlled) gear grinding machine for automobile plants. This NC machine requites high-accuracy synchronization between the grinding spindle and workspindle. We must use high-power servomotors and servo-amplifiers to satisfy the specification required for high-speed grinding. However, since the high power servo-amplifier causes very large ripple of motor current at PWM (pulsewidth modulation) frequency and induces strong noise, it becomes difficult to get the stable synchronous rotation among spindles. Therefore, the authors tried to use two-phase type PLL to achieve noise-free high-speed synchronous spindles and to reduce the noise caused by the current ripple with a kind of current filter. In this paper, an approach for suppressing the noise and experimental results are described.