Discovery of Novel 2-Carbamoyl Morpholine Derivatives as Highly Potent and Orally Active Direct Renin Inhibitors.

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin, the first and rate-limiting enzyme of the RAAS, is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. Therefore, various direct renin inhibitors (DRIs) have been researched over recent decades; however, most exhibited poor pharmacokinetics and oral bioavailability due to the peptidomimetic or nonpeptidomimetic structures with a molecular weight (MW) of >600, and only aliskiren is approved. This study introduces a novel class of DRIs comprised of a 2-carbamoyl morpholine scaffold. These compounds have a nonpeptidomimetic structure and a MW of <500. The representative compound 26 was highly potent despite not occupying S1'-S2' sites or the opened flap region used by other DRIs and exerted a significant antihypertensive efficacy via oral administration on double transgenic mice carrying both the human angiotensinogen and the human renin genes.

Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor.

Renin is the rate-limiting enzyme in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure and renal function and hence is an attractive target for the treatment of hypertension and cardiovascular/renal diseases. However, the development of direct renin inhibitors (DRIs) with favorable oral bioavailability has been a longstanding challenge for many years. This problem was thought to be because most of the reported DRIs were peptide-like structures or nonpeptide-like structures with a molecular weight (MW) of > 600. Therefore, we tried to find nonpeptidomimetic DRIs with a MW of < 500 and discovered the promising 2-carbamoyl morpholine derivative 4. In our efforts to improve the pharmacokinetic profile of 4 without a significant increase in the MW, we discovered compound 18 (SPH3127), which demonstrated higher bioavailability and a more potent antihypertensive effect in preclinical models than aliskiren and has completed a phase II clinical trial for essential hypertension.

2-(Pyridinium-1-yl)-1,1-bis(perfluoroalkylsulfonyl)ethan-1-ide: A Practical Reagent for Synthesis of Strongly Acidic 1,1-Bis(perfluoroalkylsulfonyl)alkanes.

On mixing (Rf SO2 )2 CH2 (Rf =perfluoroalkyl), paraformaldehyde, and substituted pyridines, a three-component reaction proceeded smoothly to give unusual zwitterions bearing both pyridinium and stabilized carbanion moieties in good to excellent yields. Of these, 2-fluoropyridinium derivatives rapidly dissociated in acetonitrile to give equilibrium mixtures of the zwitterions and (Rf SO2 )2 C=CH2 /2-fluoropyridine, as confirmed by detailed variable-temperature NMR studies. The dynamic behavior of such 2-fluoropyridinium compounds allows them to be used as shelf-stable, easy-to-handle sources of (Rf SO2 )2 C=CH2 . With these reagents, strongly acidic carbon acids (Rf SO2 )2 CHR were synthesized, which served as a new type of acid catalysts. Moreover, C-C bond-forming reactions with a ketene silyl acetal proceeded efficiently with Tf2 C=CH2 generated in situ.

2-(Pyridinium-1-yl)-1,1-bis(triflyl)ethanides: structural behaviour and availability as bis(triflyl)ethylating reagents.

Stable and easy-to-handle zwitterions containing carbanion and pyridinium moieties were synthesized, and their structural studies by both X-ray crystallography and theoretical methods revealed the stereoelectronic effect in the zwitterionic 'C(-)-C-N(+)' system.

Quantitative analyses of high-resolution 3D MR images of highly myopic eyes to determine their shapes.

PURPOSE: We analyzed the symmetry and pointedness of the posterior segment of highly myopic eyes. METHODS: We studied 234 eyes of 117 patients with bilateral high myopia (refractive error ≤-8.00 diopters [D]) and 40 eyes of 20 patients with emmetropia (refractive error between -1.0 and +1.0 D). Volume renderings of high-resolution magnetic resonance (MR) images were performed to obtain 3D images of the eye. To analyze the symmetry and pointedness of the posterior surface, a software was developed to measure the area and angle of a fan-shaped segment formed by selected points on the MR images. RESULTS: All of the emmetropic eyes were symmetrical in the horizontal and sagittal planes with no deformity. In highly myopic eyes, the shape was symmetrical in the horizontal plane in 146 eyes (62.4%) and in the sagittal plane in 162 (69.2%). The shape of the posterior pole was pointed (angle of fan-shaped segment <150°) in 45.7% and blunted (angle ≥150°) in 54.3% of highly myopic eyes. The most common shape was symmetrical in the horizontal and sagittal planes, and the posterior surface was blunt. The shape of the two eyes of the same individual was the same in 61 of 117 patients (52.1%). In 56 patients whose two eyes had different shapes, the most frequent pattern was a difference in the pointedness (51.8%). CONCLUSIONS: Quantitative assessments of the shape of eyes were useful in determining the pattern of eye shape deformity specific to pathologic myopia.

Guinea Pig Maximization Test of tri-ethylene glycol mono-methacrylate.

The aim of this study was to evaluate tri-ethylene glycol mono-methacrylate (TEGMA) in terms of dermatological allergic reaction using a Guinea Pig Maximization Test. Skin reaction was evaluated according to the criteria of International Contact Dermatitis Research Group. TEGMA, as a constituent in new primers, has been reported to contribute to a priming ability similar to that of highly purified glyceryl mono-methacrylate (GM). In this study, it was found that its adverse effect was less than that of 2-hydroxy ethyl methacrylate (2-HEMA), but similar to that of highly purified GM. In conclusion, it was anticipated that TEGMA would hereafter replace 2-HEMA as a primer, as it posed a lower risk of triggering dermatological allergic reaction.

Contraction gap versus shear bond strength of dentin adhesive in sound and sclerotic dentins.

To evaluate the effect of a dentin adhesive on sclerotic dentin, contraction gap width and shear bond strength were measured. Dentin cavity wall was pretreated with an experimental dentin bonding system with and without a dentin primer, or with a commercial dentin bonding system. In the experimental dentin bonding groups, contraction gap width of sclerotic dentin was significantly smaller than that of sound dentin when the cavity was not primed with glyceryl monomethacrylate. For each individual tooth, the correlation between contraction gap width and shear bond strength was insignificant. In conclusion, the bonding efficacy of dentin bonding systems to sclerotic dentin was superior to that of sound dentin. Further, it was determined that it was impossible to detect the interaction between the polymerization contraction stress of resin composites and the efficacy of dentin adhesives by measuring bond strength.

[A case of cerebral venous angioma with paresis of the left arm and face].

A 75-year-old woman was admitted to our hospital because of sudden onset of paresis in her left arm and face. She had untreated hypertension and hyperlipidemia. When she came back home after playing with children in the park, she felt weakness in her left hand. On admission, physical examination revealed that her blood pressure was very high (200/102 mmHg). Only slight weakness in her left arm and left facial palsy were recognized neurologically. An electroencephalogram showed normal findings. Brain CT and MRI revealed a venous angioma near the right central sulcus. Gadolinium-DTPA enhanced MRI showed a group of small radiating veins (so called "the caput medusae sign") connected to the venous angioma. The remaining symptoms decreased with the normalization of blood pressure. It is suggested the intracranial motor tracts of the face and arm in the precentral gyrus are adjacent to the location of this venous angioma. The dilation of venous angioma due to high blood pressure was thought to cause the paresis of face and arm in this patient.

[Analysis of brain images in patients with spinocerebellar degeneration; using statistical parametric mapping (SPM) and easy Z score imaging system (eZIS)].

In order to investigate the cerebral blood flow objectively, the easy Z score imaging system (eZIS), was developed, and has been applied in clinical practice. SPECT with 99mTc-ethyl cysteinate dimer (99mTc-ECD) was performed, and the images were analyzed using the SPM97 and the eZIS Ver. 2 to investigate cerebral blood flow in patients with two types of spino-cerebellar degeneration. We compared the distribution of cerebral blood flow between 13 patients with cortical cerebellar atrophy (CCA) and 26 patients with olivopontocerebellar atrophy (OPCA). In the both groups, cerebellar blood flow was decreased generally. In our evaluation using the eZIS Z score, the scores for the brain stem and cerebellar nucleus in the OPCA group were lower than those in the CCA group. This method facilitates the objective evaluation of cerebral blood flow in patients with spinocerebellar degeneration, and may be useful for analyzing the condition of these disease.

[A case of ventriculitis with bacterial meningitis occurred during the treatment of liver abscess].

A 47-case-year old male was admitted to our hospital because of high fever and general fatigue. He had no immune deficiency, and had no other disease in his past history. On admission, the white blood cell count and C-reacted protein were severely elevated (18,700/microliter, 27.7 mg/dl, respectively) and abdominal CT revealed multiple low density, From these results, he was diagnosed as liver abscess. Intravenous MINO and SBT/CPZ injection were started. On the fifth hospital day, he suffered from headache and nuchal rigidity. The clinical data revealed the cerebro-spinal fluid (CSF) counting 8,336 cells/mm3 (mononuclear 8,000,) protein at 119 mg/dl, and sugar 42 mg/dl. CSF cultures were negative, but Klebsiella was recognized in the blood culture and drainage fluid in liver abscess. This condition was diagnosed as bacterial meningitis and antibiotics were changed to intravenous CTRX and MEPM. Furthermore we administered oral PSL and intravenous steroid-pulse therapy. After these combination therapies his condition improved gradually. After 40 hospital day, however, he suddenly had double vision, Axial FLAIR (SE6,000/120) image revealed with high signal intensity at 4th ventricle. Intravenous MEPM was administered again. On the 60th hospital day, double vision was gradually improved and abnormal intensity at 4th ventricle was almost disappeared. This case may provide us a considerable suggestion on the treatment of bacterial meningitis.

Reversible ischemic neurological deficit (RIND) due to exercise testing for the diagnosis of angina pectoris.

A 57 year old Japanese male with chest oppression due to exercise is presented. This symptom was likely due to effort angina pectoris. Master's double two-step test revealed ischemic ST segment depression on the electrocardiogram, thus, a Tl201 myocardial stress imaging test using a bicycle ergometer was undertaken. Immediately following the exercise test, the patient experienced dizziness and palsy in his left upper and lower limbs. Cerebral angiography demonstrated 70% stenosis at the right internal carotid artery, but no abnormal findings were demonstrated on a cranial x-ray CT scan and magnetic resonance imaging. His palsy in the left limbs completely recovered within 3 weeks. Thus this event was diagnosed as a reversible ischemic neurological deficit (RIND). Major but non-cardiogenic complications during exercise testing are very rare, and RIND has not been reported thus far to the best of our knowledge.

[A case of a middle-age man with equinovarus movement at the end of the swing phase of walking].

We present a case with walking-induced equinovarus caused by dystonic contraction of the left ankle. This abnormal motor behavior occurred only when the patient walked, more specifically when the left leg was at the end of the swing phase. Surface electromyography confirmed continuous abnormal discharges in the left gastrocnemius muscles during the swing phase of walking. Brain and spinal magnetic resonance imagings (MRIs) were normal. The patient was unresponsive to drug therapy. However, the symptom reduced by the attachment of the short leg brace. From the effectiveness of the brace in normalizing, the patient was diagnosed with task-specific focal dystonia of the left leg.