Astellas Research Technologies Co.

Ōsaka, Japan

Astellas Research Technologies Co.

Ōsaka, Japan
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Niikura K.,Astellas Research Technologies Co. | Takahashi Y.,Astellas Research Technologies Co. | Iino M.,Astellas Research Technologies Co. | Funatsu Y.,Astellas Research Technologies Co. | Matsuda R.,Astellas Research Technologies Co.
European Journal of Pharmaceutical Sciences | Year: 2017

Neuropathic pain patients are characterized by evoked pain (hyperalgesia and allodynia) and spontaneous pain, the latter of which is the predominant symptom. In animal models of neuropathic pain, effects of test compounds on spontaneous pain-related behaviors have been evaluated by direct visual observation. In addition, by performing another locomotor activity experiment in normal animals, it is also indispensable to examine whether test compounds cause motor impairment to avoid overestimation of their analgesic activities. In the present study, we developed spontaneous pain-specific and automated evaluation method by improving a previous method for measuring movements of the injured hind limb in unilateral chronic constriction nerve injury (CCI) rats. Rats with unilateral CCI were implanted with strong and weak magnets in each hind limb, respectively. Limb movements were automatically detected as spiked waveforms in electromagnetic field analyzing system. Movements in each limb were analyzed separately according to differences in their respective wave amplitudes, and aberrant movements of injured limb were specifically detected on basis of the asymmetry between injured and uninjured limb movements. Consequently, the incidence ratio of spontaneous pain in injured limb, which was not affected by individual locomotive activities, was able to be obtained as a new evaluation index. The incidence ratio of spontaneous pain revealed substantial difference between CCI and sham rats with only a small variation in the value. Further, according to the frequency of movement of the uninjured limb, it could be determined simultaneously whether a test compound causes sedative effect or not, resulting in eliminating the need for another experiment in normal animals. © 2016 Elsevier B.V.


Shirakawa T.,Astellas Pharma Inc. | Shirakawa T.,Tokyo Medical University | Nakano K.,Astellas Research Technologies Co. | Hachiya N.,Tokyo Medical University | And 2 more authors.
Neuroscience Research | Year: 2011

The P2 family of receptors for adenosine 5'-triphosphate (ATP) is involved in several neuronal and glial cell functions in the central nervous system (CNS), and impaired function of these receptors is associated with both neuronal and glial dysfunction. Using quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemical analysis, we examined the expression profiles of P2 subtype receptors in the rat hippocampus following treatment with the neurotoxicant trimethyltin (TMT). Among the subtypes, P2X 1 exhibited a unique profile, with an increase in expression prior to the onset of cell death after TMT administration, and a gradual decrease thereafter in neuronal cells in the rat hippocampus. This expression pattern was similar to that of cyclooxygenase-2 (COX-2) following TMT administration. The P2X 1 antagonist NF499 strongly prevented neuronal cell death induced by TMT in the CA1 region, and successfully suppressed locomotor hyperreactivity. Furthermore, NF449 administration also inhibited COX-2 expression in the CA1 region on day 3 following TMT treatment, whereas no change was observed in the CA3. These findings suggest that P2X 1 plays a primary role in TMT-induced neuronal cell death in the CA1 region. © 2011 Elsevier Ireland Ltd and the Japan Neuroscience Society.


Ohsumi K.,Astellas Pharma Inc. | Masaki T.,Astellas Research Technologies Co. | Takase S.,Astellas Pharma Inc. | Watanabe M.,Astellas Pharma Inc. | Fujie A.,Astellas Pharma Inc.
Journal of Antibiotics | Year: 2014

A novel antifungal agent, AS2077715, was isolated from the fermentation broth of a fungal strain (339855) identified as a new Capnodium species based on morphological characteristics and large-subunit ribosomal DNA sequencing. AS2077715 was isolated as a white powder via solvent extraction, HP-20 and ODS-B column chromatography and crystallization, and was determined to have the molecular formula C 25 H 41 NO 7. AS2077715 has a structure related to that of funiculosin, an inhibitor of mitochondrial cytochrome bc 1 complex (complex III), and showed antifungal activity against Trichophyton species.


Yamamoto E.,Astellas Research Technologies Co. | Muramatsu H.,Astellas Research Technologies Co. | Nagai K.,Astellas Research Technologies Co.
International journal of systematic and evolutionary microbiology | Year: 2014

Two myxobacterial strains (designated B00001(T) and B00002(T)) were isolated from forest soil samples collected from Yakushima Island, Kagoshima, Japan. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strains B00001(T) and B00002(T) respectively formed independent branches within the suborders Cystobacterineae and Sorangiineae and were most closely related to Cystobacter armeniaca DSM 14710(T) (90.4% similarity) and Byssovorax cruenta DSM 14553(T) (91.3%). Neither strain showed typical features of myxobacteria such as bacteriolytic action or fruiting body formation, but both had high DNA G+C contents (66.3-68.3 mol%). Swarming motility was observed in strain B00002(T) only. Cells of both strains were vegetative, chemoheterotrophic, mesophilic, strictly aerobic, Gram-negative, motile rods, and both strains exhibited esterase lipase (C8), leucine arylamidase, naphthol-AS-BI-phosphohydrolase and β-galactosidase activities. Strain B00001(T) contained MK-7 as the predominant respiratory quinone and the major fatty acid was iso-C15:0. In contrast, strain B00002(T) contained MK-8 as the major cellular quinone and the major fatty acids were C16 : 1ω5c and iso-C17 : 0. Based on the phenotypic and genotypic data presented, strains B00001(T) and B00002(T) represent novel genera and species, for which we propose the names Vulgatibacter incomptus gen. nov., sp. nov. and Labilithrix luteola gen. nov., sp. nov., respectively. The type strains of Vulgatibacter incomptus and Labilithrix luteola are B00001(T) ( = NBRC 109945(T) = DSM 27710(T)) and B00002(T) ( = NBRC 109946(T) = DSM 27648(T)), respectively. The new genera are assigned to the new families Vulgatibacteraceae fam. nov. and Labilitrichaceae fam. nov., respectively. In addition, Anaeromyxobacteraceae fam. nov., is proposed to accommodate the genus Anaeromyxobacter, which is related to the genus Vulgatibacter. © 2014 IUMS.


Nagashima T.,Astellas Pharma Inc. | Shigematsu N.,Astellas Research Technologies Co. | Maruki R.,Astellas Research Technologies Co. | Urano Y.,Astellas Pharma Inc. | And 4 more authors.
Molecular Pharmacology | Year: 2010

Excessive hepatic glucose production through the gluconeogenesis pathway is partially responsible for the elevated glucose levels observed in patients with type 2 diabetes mellitus (T2DM). The forkhead transcription factor forkhead box O1 (Foxo1) plays a crucial role in mediating the effect of insulin on hepatic gluconeogenesis. Here, using a db/db mouse model, we demonstrate the effectiveness of Foxo1 inhibitor, an orally active small-molecule compound, as a therapeutic drug for treating T2DM. Using mass spectrometric affinity screening, we discovered a series of compounds that bind to Foxo1, identifying among them the compound, 5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4- dihydroquinoline-3-carboxylic acid (AS1842856), which potently inhibits human Foxo1 transactivation and reduces glucose production through the inhibition of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase mRNA levels in a rat hepatic cell line. Oral administration of AS1842856 to diabetic db/db mice led to a drastic decrease in fasting plasma glucose level via the inhibition of hepatic gluconeogenic genes, whereas administration to normal mice had no effect on the fasting plasma glucose level. Treatment with AS1842856 also suppressed an increase in plasma glucose level caused by pyruvate injection in both normal and db/db mice. Taken together, these findings indicate that the Foxo1 inhibitor represents a new class of drugs for use in treating T2DM. Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics.


PubMed | Astellas Research Technologies Co. and Astellas Pharma Inc.
Type: Journal Article | Journal: The Journal of antibiotics | Year: 2015

FR901459, a product of the fungus Stachybotrys chartarum No. 19392, is a derivative of cyclosporin A (CsA) and a powerful immunosuppressant that binds cyclophilin. Recently, it was reported that CsA was effective against hepatitis C virus (HCV). However, FR901459 lacks active moieties, which are essential for synthesizing more potent and safer derivatives of this anti-HCV agent. Here we identified an actinomycete strain (designated 7887) that was capable of efficient bioconversion of FR901459. Structural elucidation of the isolated bioconversion products (1-7) revealed that compounds 1-4 were mono-hydroxylated at the position of 1-MeBmt or 9-MeLeu, whereas compounds 5-7 were bis-hydroxylated at both positions. The results of morphological and chemical characterization, as well as phylogenetic analysis of 16S ribosomal DNA (rDNA), suggested that strain 7887 belonged to the genus Lentzea. Comparison of the FR901459 conversion activity of strain 7887 with several other Lentzea strains revealed that although all examined strains metabolized FR901459, strain 7887 had a characteristic profile with respect to bioconversion products. Taken together, these findings suggest that strain 7887 can be used to derivative FR901459 to produce a chemical template for further chemical modifications that may provide more effective and safer anti-HCV drugs.


PubMed | Astellas Research Technologies Co.
Type: Evaluation Studies | Journal: Assay and drug development technologies | Year: 2015

Transport assays using P-gp-expressing cell lines are commonly used to identify P-gp substrates and inhibitors in drug discovery. The P-gp cell-based assay is performed manually in 12- or 24-well plates and requires improvement for high-throughput screening. In this study, we established an efficient semiautomated 96-well transport assay using LLC-PK1 cells transfected with human P-gp. The protocol was optimized with a microplate washer for exchanging media and buffer to enhance throughput. P-gp substrates and inhibitors, and the paracellular marker Dextran Texas Red were used to validate the 96-well transport assay. Cell monolayer integrity after washing by a microplate washer was confirmed by measuring paracellular permeability of Dextran Texas Red. Permeability and net flux ratio of the P-gp substrates and the inhibitory potency of the P-gp inhibitors were comparable in 24- and 96-well plates. The regression value of net flux ratio of P-gp substrates was high between the two formats (r=0.99). The optimized 96-well transport assay using the microplate washer was found to be an efficient high-throughput screening tool that provided the same quality data as the 24-well plate for the identification of P-gp substrates and inhibitors in drug discovery.


PubMed | Astellas Research Technologies Co.
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

Neuropathic pain patients are characterized by evoked pain (hyperalgesia and allodynia) and spontaneous pain, the latter of which is the predominant symptom. In animal models of neuropathic pain, effects of test compounds on spontaneous pain-related behaviors have been evaluated by direct visual observation. In addition, by performing another locomotor activity experiment in normal animals, it is also indispensable to examine whether test compounds cause motor impairment to avoid overestimation of their analgesic activities. In the present study, we developed spontaneous pain-specific and automated evaluation method by improving a previous method for measuring movements of the injured hind limb in unilateral chronic constriction nerve injury (CCI) rats. Rats with unilateral CCI were implanted with strong and weak magnets in each hind limb, respectively. Limb movements were automatically detected as spiked waveforms in electromagnetic field analyzing system. Movements in each limb were analyzed separately according to differences in their respective wave amplitudes, and aberrant movements of injured limb were specifically detected on basis of the asymmetry between injured and uninjured limb movements. Consequently, the incidence ratio of spontaneous pain in injured limb, which was not affected by individual locomotive activities, was able to be obtained as a new evaluation index. The incidence ratio of spontaneous pain revealed substantial difference between CCI and sham rats with only a small variation in the value. Further, according to the frequency of movement of the uninjured limb, it could be determined simultaneously whether a test compound causes sedative effect or not, resulting in eliminating the need for another experiment in normal animals.


Yoshida S.,Astellas Pharma Inc. | Kasai M.,Astellas Pharma Inc. | Kimura T.,Astellas Research Technologies Co. | Akiba T.,Astellas Pharma Inc. | And 2 more authors.
Organic Process Research and Development | Year: 2012

Process research and development of a practical and scalable synthetic route toward compound (S)-1 and compound (R)-1, which are potent selective dual antagonists for 5-HT2B and 5-HT7 receptors, respectively, is described. The medicinal chemistry route and second generation route were also unattractive for large-scale use for a variety of reasons. The new synthetic method does not require any purification by column chromatography for all steps and highly exothermic reactions. Additionally, we developed an efficient method of optical resolution in which each carboxylic acid isomer was separated with chiral amine in high yield and high enantiopurity. This highly efficient and scalable process was successfully demonstrated in the large scale synthesis of compound (S)-1 and compound (R)-1 in high enantiopurity. © 2012 American Chemical Society.


PubMed | Astellas Research Technologies Co.
Type: Journal Article | Journal: The Journal of veterinary medical science | Year: 2016

To determine the effect of long-distance (approximately 600 km) road transportation on the blood biochemistry of laboratory animals, we investigated the changes in serum biochemical parameters in healthy cynomolgus monkeys and beagle dogs transported by truck from Osaka to Tsukuba, Japan. The concentrations of serum cortisol, total bilirubin and aspartate aminotransferase in monkeys increased during transportation. Serum cortisol and total bilirubin levels in dogs also increased during transportation, but serum triglyceride decreased. Serum parameter values in truck-transported monkeys and dogs returned to baseline levels within two weeks following arrival. Taken together, these results suggest that a two-week acclimation period is the minimum duration required for adaptation following road transportation.

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