Publications by authors named "Hidenori Kimura"

35 Publications

Features of post-endoscopic submucosal dissection electrocoagulation syndrome for early gastric neoplasm.

J Gastroenterol Hepatol 2021 Jun 15. Epub 2021 Jun 15.

Division of Endoscopy, Shizuoka Cancer Center, Nagaizumi, Japan.

Background And Aim: Post-endoscopic submucosal dissection electrocoagulation syndrome (PECS) has become a common adverse event after colorectal endoscopic submucosal dissection (ESD) and esophageal ESD. However, little is known about PECS after gastric ESD. Therefore, this study aimed to investigate the clinical features of PECS after gastric ESD.

Methods: Patients who underwent ESD for gastric cancer or adenoma between January 2016 and December 2017 were retrospectively investigated. PECS was clinically diagnosed based on the presence of upper abdominal pain and localized abdominal tenderness with a temperature of >37.5°C, without perforation. We analyzed the clinical features of PECS.

Results: A total of 637 ESD cases were enrolled; PECS occurred in 32 patients (5.0%), all of whom were diagnosed on postoperative Day 1. Among PECS cases, unplanned prolongation of hospitalization or fasting period was observed in 15 patients (47%). As a result, the median durations of hospitalization and fasting period were significantly longer in PECS cases (P = 0.008 and P < 0.001, respectively); however, the mean differences were less than a day. Additionally, all PECS cases recovered with conservative treatment.

Conclusions: PECS is considered a common adverse event after gastric ESD. More than half of patients with PECS could start diets and be discharged as well as those without PECS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgh.15583DOI Listing
June 2021

Discovery of N-(6-(5-fluoro-2-(piperidin-1-yl)phenyl)pyridazin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide as a brain-permeable and metabolically stable kynurenine monooxygenase inhibitor.

Bioorg Med Chem Lett 2021 Jul 17;44:128115. Epub 2021 May 17.

Drug Research Division, Sumitomo Dainippon Pharma. Co., Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address:

Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington's disease (HD). This study presents the structure-activity relationship of pyridazine derivatives to find novel KMO inhibitors. The most promising compound 14 resolved the problematic issues of lead compound 1, i.e., metabolic instability and reactive metabolite-derived side-effects. Compound 14 exhibited high brain permeability and a long-lasting pharmacokinetics profile in monkeys, and neuroprotective kynurenic acid was increased by a single administration of 14 in R6/2 mouse brain. These results demonstrated 14 may be a potential drug candidate to treat HD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2021.128115DOI Listing
July 2021

Long-term outcomes of salvage endoscopic submucosal dissection for local failure after chemoradiotherapy for esophageal squamous cell carcinoma.

Jpn J Clin Oncol 2021 Jul;51(7):1036-1043

Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan.

Background: Salvage endoscopic submucosal dissection is considered a minimally invasive treatment for local failure after chemoradiotherapy for esophageal squamous cell carcinoma. However, the long-term outcomes have not been fully evaluated. This study investigated the short-term and long-term outcomes of salvage endoscopic submucosal dissection.

Methods: Patients who underwent endoscopic submucosal dissection for local recurrence or residual tumor after chemoradiotherapy from January 2006 to December 2017 were retrospectively investigated. Follow-up included endoscopic examination and computed tomography at least once every 6 months after salvage endoscopic submucosal dissection. Risk factors for disease recurrence after salvage endoscopic submucosal dissection were assessed using the Cox hazards model.

Results: A total of 30 patients (33 cases of esophageal squamous cell carcinoma: local recurrence, n = 27; residual tumor, n = 6) were included. The median endoscopic submucosal dissection procedure time was 40 min (interquartile range [IQR], 33-58.5 min). En bloc resection was achieved in 31 (94%) of 33 esophageal squamous cell carcinoma cases. One patient with intraoperative perforation did not require surgical intervention and recovered with conservative treatment. A total of 16 patients (53%) had disease recurrence at a median follow-up of 51 months (IQR, 33-81 months). The 3-year overall, disease-specific, recurrence-free and local recurrence-free survival rates were 75%, 82%, 58% and 90%, respectively. The positive vertical margin, submucosal invasion in the endoscopic submucosal dissection specimen and piecemeal resection were significantly associated with disease recurrence after salvage endoscopic submucosal dissection.

Conclusions: Salvage endoscopic submucosal dissection is a feasible treatment for local failure after chemoradiotherapy for esophageal squamous cell carcinoma with acceptable long-term outcomes. However, for cases with positive vertical margins and submucosal invasion in the endoscopic submucosal dissection specimen, salvage endoscopic submucosal dissection outcomes were insufficient and additional treatment might be required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jjco/hyab027DOI Listing
July 2021

N-(6-phenylpyridazin-3-yl)benzenesulfonamides as highly potent, brain-permeable, and orally active kynurenine monooxygenase inhibitors.

Bioorg Med Chem Lett 2021 02 28;33:127753. Epub 2020 Dec 28.

Drug Research Division, Sumitomo Dainippon Pharma. Co., Ltd., 3-1-98, Kasugade-naka, Konohana-ku, Osaka 554-0022, Japan. Electronic address:

Huntington's disease (HD) is one of the serious neurodegenerative diseases and no disease modifiers are available to date. The correction of unbalanced kynurenine pathway metabolites may be useful to treat disease progression and kynurenine monooxygenase (KMO) is considered an ideal drug target. A couple of KMO inhibitors have been reported, but their brain permeability was very poor. We found pyridazinylsulfonamide as a novel lead compound, and it was optimized to the brain-permeable and highly potent KMO inhibitor 12, which was equipotent with CHDI-340246 and superior to CHDI-340246 in terms of brain penetration. Compound 12 was effective in R6/2 mice (HD model mice), i.e. neuroprotective kynurenic acid was increased, whereas neurotoxic 3-hydroxykynurenine was suppressed. In addition, impaired cognitive function was improved. Therefore, the brain-permeable KMO inhibitor was considered to be a disease modifier for HD treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2020.127753DOI Listing
February 2021

Pretreatment predictive factors for feasibility of oral intake in adjuvant concurrent chemoradiotherapy for patients with locally advanced squamous cell carcinoma of the head and neck.

Int J Clin Oncol 2020 Feb 16;25(2):258-266. Epub 2019 Oct 16.

Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.

Background: Prophylactic percutaneous endoscopic gastrostomy (PEG) has been widely performed before concurrent chemoradiotherapy (CCRT) for locally advanced squamous cell carcinoma of the head and neck (LASCCHN) because severe oral mucositis and dysphagia induced by CCRT lead to difficulty with oral intake. However, it is controversial whether all patients require prophylactic PEG for adjuvant CCRT. This study evaluated predictive factors for the feasibility of oral intake in adjuvant CCRT for patients with LASCCHN.

Methods: This study retrospectively analyzed 117 LASCCHN patients who underwent surgery followed by adjuvant CCRT with cisplatin at Shizuoka Cancer Center between April 2008 and December 2018. To investigate predictive factors for the feasibility of oral intake, tumor factors, treatment factors and social factors were included in multivariate analyses.

Results: Of the 117 patients, 25 received total laryngectomy and 92 received other surgery. In multivariate analysis, total laryngectomy [HR (hazard ratio) 0.09, P = 0.001] and oral cavity of primary tumor location (HR 0.21, P = 0.031) were significantly associated with the feasibility of oral intake. Difficulty obtaining adequate nutrition via oral intake from initiation of CCRT until 1 year after its completion was significantly rarer in the total laryngectomy group than in the other surgery group (16% vs. 57%, P < 0.001).

Conclusion: Our study suggests that majority of patients who underwent total laryngectomy are able to maintain oral intake during adjuvant chemoradiotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10147-019-01560-5DOI Listing
February 2020

Preoperative indicators of misdiagnosis in invasion depth staging of esophageal cancer: Pitfalls of magnifying endoscopy with narrow-band imaging.

Dig Endosc 2020 Jan 18;32(1):56-64. Epub 2019 Jul 18.

Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan.

Objectives: The Japan Esophageal Society classification has been widely applied for predicting the invasion depth of superficial esophageal squamous cell carcinomas (SESCCs). Although Type B2 of the classification clinically corresponds to SESCCs with muscularis mucosa or slight submucosal invasion (MM/SM1), diagnostic yield based on Type B2 is insufficient. This study aimed to investigate risk factors for misdiagnosis in preoperative invasion depth staging.

Methods: We included a total of 104 SESCCs in which Type B2 was observed by magnifying endoscopy. SESCCs were classified as either correct diagnosis (pMM/SM1, 39 lesions), overdiagnosis (epithelium or the lamina propria [pEP/LPM], 34 lesions), or underdiagnosis (deep invasion into the submucosa [pSM2-3], 31 lesions) based on pathological depth of invasion. The association between misdiagnosis and endoscopic features, including distinct features, was evaluated using logistic regression analysis. Distinct features were defined as nodular protrusion, thickness, and/or clearly depressed area. The diameter of type B2 area was endoscopically measured, and the cut-off value was determined using a receiver operating characteristic curve.

Results: Type B2 area <6 mm (area under the curve, 0.776) and Type B2 vessels around erosion were significantly associated with overdiagnosis (odds ratio, 16.6 and 11.0, respectively), while distinct features were significantly associated with underdiagnosis (odds ratio, 8.7). Adjusted by these misdiagnosis factors, positive predictive value of Type B2 significantly improved from 38% to 65% (P < 0.01).

Conclusions: Lesions with a small Type B2 area (<6 mm) and/or Type B2 vessels around erosion should be diagnosed as EP/LPM and lesions with distinct features as SM2-3.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/den.13464DOI Listing
January 2020

A huge inflammatory fibroid polyp: an unexpected finding after positive fecal immunochemical test.

Endoscopy 2019 06 25;51(6):E147-E148. Epub 2019 Mar 25.

Division of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/a-0862-0133DOI Listing
June 2019

Mathematical modeling of septic shock based on clinical data.

Theor Biol Med Model 2019 03 6;16(1). Epub 2019 Mar 6.

Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo, Japan.

Background: Mathematical models of diseases may provide a unified approach for establishing effective treatment strategies based on fundamental pathophysiology. However, models that are useful for clinical practice must overcome the massive complexity of human physiology and the diversity of patients' environmental conditions. With the aim of modeling a complex disease, we choose sepsis, which is highly complex, life-threatening systemic disease with high mortality. In particular, we focused on septic shock, a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality. Our model includes cardiovascular, immune, nervous system models and a pharmacological model as submodels and integrates them to create a sepsis model based on pathological facts.

Results: Model validation was done in two steps. First, we established a model for a standard patient in order to confirm the validity of our approach in general aspects. For this, we checked the correspondence between the severity of infection defined in terms of pathogen growth rate and the ease of recovery defined in terms of the intensity of treatment required for recovery. The simulations for a standard patient showed good correspondence. We then applied the same simulations to a patient with heart failure as an underlying disease. The model showed that spontaneous recovery would not occur without treatment, even for a very mild infection. This is consistent with clinical experience. We next validated the model using clinical data of three sepsis patients. The model parameters were tuned for these patients based on the model for the standard patient used in the first part of the validation. In these cases, the simulations agreed well with clinical data. In fact, only a handful parameters need to be tuned for the simulations to match with the data.

Conclusions: We have constructed a model of septic shock and have shown that it can reproduce well the time courses of treatment and disease progression. Tuning of model parameters for each patient could be easily done. This study demonstrates the feasibility of disease models, suggesting the possibility of clinical use in the prediction of disease progression, decisions on the timing of drug dosages, and the estimation of time of infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12976-019-0101-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404291PMC
March 2019

[A case of liver Mycobacterium avium complex syndrome, diagnosed by liver biopsy].

Nihon Shokakibyo Gakkai Zasshi 2018;115(9):818-824

Department of Pathology, Otsu City Hospital.

A man in his 70s was referred to our hospital for evaluation of low-grade fever, weight loss, and liver dysfunction. Serological tests for viral hepatitis or autoimmune diseases were negative. No significant findings were observed on whole-body computed tomography (CT). Histopathologic examination of a liver biopsy sample revealed a non-caseating granuloma with acid-fast bacillus using the Ziehl-Neelsen stain. Serum Mycobacterium avium complex (MAC) antibody was positive. We started treatment for pulmonary MAC disease. His clinical condition and liver function improved within two months. He was diagnosed with liver MAC disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11405/nisshoshi.115.818DOI Listing
June 2019

A mathematical model of type 1 diabetes involving leptin effects on glucose metabolism.

J Theor Biol 2018 11 8;456:213-223. Epub 2018 Aug 8.

Faculty of Science and Engineering, Waseda University, Building 55S, Room 706A, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan. Electronic address:

Leptin, a hormone released from fat cells in adipose tissues, was recently found to be capable of normalizing glucose metabolism in animals. Clinical data on patients with lipodystrophy indicates that leptin may have a positive effect on glucose metabolism in individuals with diabetes. There are growing expectations that leptin can improve the current insulin treatment for patients with type 1 diabetes. We investigated this possibility through in silico experiments based on a mathematical model of diabetes, which is currently the only mode of research that eliminates human risk. A model of the brain-centered glucoregulatory system, in which leptin plays a central role, was constructed and integrated within a conventional model of insulin/glucose dynamics. The model has been validated using experimental data from animal studies. The in silico combination experiments showed excellent therapeutic performance over insulin monotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtbi.2018.08.008DOI Listing
November 2018

Phase-transfer-catalysed asymmetric synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones.

Chem Commun (Camb) 2018 Jun;54(51):7078-7080

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan.

1,4-Benzoxazin-3-one is a scaffold which is found in a variety of biologically active molecules. Because of its unique structure and drug-like activities, 1,4-benzoxazin-3-ones have been widely used in drug discovery. However, just a few methods have been developed to access these molecules by catalytic asymmetric synthesis. We report herein the phase-transfer-catalysed asymmetric alkylation of 2-aryl-1,4-benzoxazin-3-ones as a new way for the highly enantioselective synthesis of 2,2-disubstituted 1,4-benzoxazin-3-ones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c8cc03635gDOI Listing
June 2018

Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors: use of a carboxylate prodrug to improve bioavailability.

Bioorg Med Chem 2015 Feb 30;23(4):779-90. Epub 2014 Dec 30.

Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd, 33-94 Enoki-cho, Suita, Osaka 564-0053, Japan.

We have previously reported a novel series of 3H-imidazo[4,5-c]quinolin-4(5H)-ones with potent dipeptidyl peptidase IV (DPP-4) inhibitory activity. However, these compounds showed poor oral absorption. We attempted in this study esterification of the carboxylic acid moiety to improve the compounds 1-4 plasma concentrations. Our efforts yielded 10h with a 5-methyl-2-oxo-1,3-dioxol-4-yl methyl ester as an S9/plasma-cleavable functionality. Compound 10h showed significantly high oral absorption and potent DPP-4 inhibition in vivo and decreased Zucker fatty rats glucose levels in the oral glucose tolerance test. Optimization of the ester moiety revealed that rapid conversion to the carboxyl form in both liver S9 fractions and serum was important for prodrugs not to be detected in the plasma after oral administration. In particular, lability in the serum was found to be an important characteristic. Through our investigation, we were able to develop a novel efficient synthetic method for construction of 3H-imidazo[4,5-c]quinolin-4(5H)-ones using intramolecular radical cyclization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2014.12.051DOI Listing
February 2015

Muscle synergy stability and human balance maintenance.

J Neuroeng Rehabil 2014 Aug 30;11:129. Epub 2014 Aug 30.

BTCC, RIKEN, Nagoya, Japan.

Background: The signals that the central nervous system (CNS) produces and sends to the muscles to effect movement are not entirely understood. Muscle synergy theory suggests that the central nervous system produces a small number of signals that pass through a network that distributes combinations of these signals to the muscles. Though these synergies are rather stable over time, some variability is present.

Methods: Here, we investigated the variability of muscle synergy and defined a synergy stability index (SSI) to quantify it. We measured the activity of muscles responsible for maintaining lateral balance in humans standing on a platform that was subjected to lateral disturbance from the platform. We then calculated muscle synergies attributed to postural reflex and automatic response by using non-negative matrix factorization (NMF). Finally, from the calculated muscle synergies, we obtained SSI.

Results: We observed a positive proportional relation between balance performance and SSI. Participants who were adept at maintaining balance were found to have invariant muscle synergies, and non-adept participants showed variable muscle synergies.

Conclusions: These results suggest that SSI can be used to quantitatively evaluate balance maintenance ability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1743-0003-11-129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4161771PMC
August 2014

Muscle synergy space: learning model to create an optimal muscle synergy.

Front Comput Neurosci 2013 15;7:136. Epub 2013 Oct 15.

Intelligent Behavior Control Unit, Brain Science Institute, BSI-TOYOTA Collaboration Center of RIKEN Nagoya, Japan.

Muscle redundancy allows the central nervous system (CNS) to choose a suitable combination of muscles from a number of options. This flexibility in muscle combinations allows for efficient behaviors to be generated in daily life. The computational mechanism of choosing muscle combinations, however, remains a long-standing challenge. One effective method of choosing muscle combinations is to create a set containing the muscle combinations of only efficient behaviors, and then to choose combinations from that set. The notion of muscle synergy, which was introduced to divide muscle activations into a lower-dimensional synergy space and time-dependent variables, is a suitable tool relevant to the discussion of this issue. The synergy space defines the suitable combinations of muscles, and time-dependent variables vary in lower-dimensional space to control behaviors. In this study, we investigated the mechanism the CNS may use to define the appropriate region and size of the synergy space when performing skilled behavior. Two indices were introduced in this study, one is the synergy stability index (SSI) that indicates the region of the synergy space, the other is the synergy coordination index (SCI) that indicates the size of the synergy space. The results on automatic posture response experiments show that SSI and SCI are positively correlated with the balance skill of the participants, and they are tunable by behavior training. These results suggest that the CNS has the ability to create optimal sets of efficient behaviors by optimizing the size of the synergy space at the appropriate region through interacting with the environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fncom.2013.00136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3796759PMC
October 2013

Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors.

Bioorg Med Chem 2012 Oct 5;20(19):5864-83. Epub 2012 Aug 5.

Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.

In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2012.07.046DOI Listing
October 2012

A catalytic asymmetric Ugi-type reaction with acyclic azomethine imines.

Angew Chem Int Ed Engl 2012 Jul 12;51(29):7279-81. Epub 2012 Jun 12.

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan.

An unconventional Ugi: A catalytic asymmetric Ugi-type reaction can be realized by use of N'-alkylbenzohydrazide, instead of a conventional amine, in the presence of an axially chiral dicarboxylic acid. The reaction proceeds through a key acyclic azomethine imine intermediate, which has recently emerged as a promising electrophile in asymmetric catalysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201201905DOI Listing
July 2012

Artificial balancer - supporting device for postural reflex.

Gait Posture 2012 Feb 12;35(2):316-21. Epub 2011 Dec 12.

RIKEN (The Institute of Physical and Chemical Research), BTCC (BSI-Toyota Collaboration Center), Anagahora, Shimoshidami Moriyama-ku, Nagoya, Japan.

The evolutionarily novel ability to keep ones body upright while standing or walking, the human balance, deteriorates in old age or can be compromised after accidents or brain surgeries. With the aged society, age related balance problems are on the rise. Persons with balance problems are more likely to fall during their everyday life routines. Especially in elderly, falls can lead to bone fractures making the patient bedridden, weakening the body and making it more prone to other diseases. Health care expenses for a fall patient are often very high. There is a great deal of research being done on exoskeletons and power assists. However, these technologies concentrate mainly on the amplifications of human muscle power while balance has to be provided by the human themself. Our research has been focused on supporting human balance in harmony with the human's own posture control mechanisms such as postural reflexes. This paper proposes an artificial balancer that supports human balance through acceleration of a flywheel attached to the body. Appropriate correcting torques are generated through our device based on the measurements of body deflections. We have carried out experiments with test persons standing on a platform subject to lateral perturbations and ambulatory experiments while walking on a balance beam. These experiments have demonstrated the effectiveness of our device in supporting balance and the possibility of enhancing balance-keeping capability in human beings through the application of external torque.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gaitpost.2011.10.002DOI Listing
February 2012

2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): a potent, orally active dipeptidyl peptidase IV inhibitor without mechanism-based inactivation of CYP3A.

Bioorg Med Chem 2011 Sep 4;19(18):5490-9. Epub 2011 Aug 4.

Drug Research Division, Dainippon Sumitomo Pharma Co. Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan.

We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2011.07.042DOI Listing
September 2011

Generation and exploitation of acyclic azomethine imines in chiral Brønsted acid catalysis.

Nat Chem 2011 Jul 22;3(8):642-6. Epub 2011 Jul 22.

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.

Successful implementation of a catalytic asymmetric synthesis strategy to produce enantiomerically enriched compounds requires the adoption of suitable prochiral substrates. The combination of an azomethine imine electrophile with various nucleophiles could give straightforward access to a number of synthetically useful chiral hydrazines, but is used rarely. Here we report the exploitation of acyclic azomethine imines as a new type of prochiral electrophile. They can be generated in situ by the condensation of N'-benzylbenzoylhydrazide with a variety of aldehydes in the presence of a catalytic amount of an axially chiral dicarboxylic acid. By trapping these electrophiles with alkyl diazoacetate or (diazomethyl)phosphonate nucleophiles, we produced a diverse array of chiral α-diazo-β-hydrazino esters and phosphonates with excellent enantioselectivities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nchem.1096DOI Listing
July 2011

Synthetic application and structural elucidation of axially chiral dicarboxylic acid: asymmetric Mannich-type reaction with diazoacetate, (diazomethyl)phosphonate, and (diazomethyl)sulfone.

J Org Chem 2011 Aug 6;76(15):6030-7. Epub 2011 Jul 6.

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan.

The past decade has witnessed the burgeoning research fields of chiral Brønsted acid catalysis. However, carboxylic acids, arguably the most general acids in organic chemistry, have rarely been used as chiral Brønsted acid catalysts. In this context, we developed axially chiral dicarboxylic acid and evaluated its catalytic activity in asymmetric Mannich-type reaction of aromatic aldehyde-derived N-Boc imines and tert-butyl diazoacetate. To demonstrate the remarkable generality of this catalytic system, tert-butyl diazoacetate was replaced with its phosphorus and sulfur analogues, (diazomethyl)phosphonate and (diazomethyl)sulfone, by which synthetically valuable chiral β-amino phosphonates and β-amino sulfones could be obtained with high enantioselectivities under identical reaction conditions. X-ray crystallographic analysis of axially chiral dicarboxylic acid complexed with a pyridine derivative revealed its unique internal hydrogen bonding, a property that serves as a basis for its distinctive acidity and chiral scaffold.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jo2005999DOI Listing
August 2011

Modular synthesis of axially chiral 3,3'-disilyl dicarboxylic acids by silalactones.

Chem Asian J 2011 Aug 12;6(8):1936-8. Epub 2011 May 12.

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/asia.201100172DOI Listing
August 2011

Discovery of new chemotype dipeptidyl peptidase IV inhibitors having (R)-3-amino-3-methyl piperidine as a pharmacophore.

Bioorg Med Chem Lett 2010 Dec 26;20(24):7246-9. Epub 2010 Oct 26.

Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, Konohana-ku, Osaka, Japan.

Structures containing the (R)-3-amino-3-methyl piperidine unit as a new pharmacophore moiety have been shown to possess moderate inhibitory activity for DPP-4 with good pharmacokinetics profile. One of these compounds was found to have good oral bioavailability and PK/PD profile in ZF-rat.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2010.10.101DOI Listing
December 2010

Enantioselective formal alkenylations of imines catalyzed by axially chiral dicarboxylic acid using vinylogous aza-enamines.

Angew Chem Int Ed Engl 2010 Sep;49(38):6844-7

Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto, 606-8502, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201003600DOI Listing
September 2010

A mathematical model of brain glucose homeostasis.

Theor Biol Med Model 2009 Nov 27;6:26. Epub 2009 Nov 27.

Brain Science Institute, the Institute of Physical and Chemical Research (RIKEN) 2271-130 Anagahora, Shimoshidami, Moriyama-ku, Nagoya, 463-0003, Japan.

Background: The physiological fact that a stable level of brain glucose is more important than that of blood glucose suggests that the ultimate goal of the glucose-insulin-glucagon (GIG) regulatory system may be homeostasis of glucose concentration in the brain rather than in the circulation.

Methods: In order to demonstrate the relationship between brain glucose homeostasis and blood hyperglycemia in diabetes, a brain-oriented mathematical model was developed by considering the brain as the controlled object while the remaining body as the actuator. After approximating the body compartmentally, the concentration dynamics of glucose, as well as those of insulin and glucagon, are described in each compartment. The brain-endocrine crosstalk, which regulates blood glucose level for brain glucose homeostasis together with the peripheral interactions among glucose, insulin and glucagon, is modeled as a proportional feedback control of brain glucose. Correlated to the brain, long-term effects of psychological stress and effects of blood-brain-barrier (BBB) adaptation to dysglycemia on the generation of hyperglycemia are also taken into account in the model.

Results: It is shown that simulation profiles obtained from the model are qualitatively or partially quantitatively consistent with clinical data, concerning the GIG regulatory system responses to bolus glucose, stepwise and continuous glucose infusion. Simulations also revealed that both stress and BBB adaptation contribute to the generation of hyperglycemia.

Conclusion: Simulations of the model of a healthy person under long-term severe stress demonstrated that feedback control of brain glucose concentration results in elevation of blood glucose level. In this paper, we try to suggest that hyperglycemia in diabetes may be a normal outcome of brain glucose homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1742-4682-6-26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2801528PMC
November 2009

Biomimetic approach to tacit learning based on compound control.

IEEE Trans Syst Man Cybern B Cybern 2010 Feb 31;40(1):77-90. Epub 2009 Jul 31.

RIKEN Brain Science Institute (BSI)-Toyota Collaboration Center, Nagoya 463-0003, Japan.

The remarkable capability of living organisms to adapt to unknown environments is due to learning mechanisms that are totally different from the current artificial machine-learning paradigm. Computational media composed of identical elements that have simple activity rules play a major role in biological control, such as the activities of neurons in brains and the molecular interactions in intracellular control. As a result of integrations of the individual activities of the computational media, new behavioral patterns emerge to adapt to changing environments. We previously implemented this feature of biological controls in a form of machine learning and succeeded to realize bipedal walking without the robot model or trajectory planning. Despite the success of bipedal walking, it was a puzzle as to why the individual activities of the computational media could achieve the global behavior. In this paper, we answer this question by taking a statistical approach that connects the individual activities of computational media to global network behaviors. We show that the individual activities can generate optimized behaviors from a particular global viewpoint, i.e., autonomous rhythm generation and learning of balanced postures, without using global performance indices.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TSMCB.2009.2014470DOI Listing
February 2010

Thermal cyclization of nonconjugated aryl-yne-carbodiimide furnishing a dibenzonaphthyridine derivative.

Chem Pharm Bull (Tokyo) 2009 Apr;57(4):393-6

The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, Osaka, Japan.

The reagent-free C(2)-C(7) thermal cyclization of a nonconjugated aryl-yne-carbodiimide yielded a dibenzo[b,g][1,8]naphthyridine derivative, whose congeners are known to possess fascinating pharmacological properties. This is the first heteroaromatic compound prepared by the thermal cycloaromatization of "nonconjugated" aryl-ynes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1248/cpb.57.393DOI Listing
April 2009

Estimation of the source-by-source effect of autorepression on genetic noise.

Biophys J 2008 Aug 4;95(3):1063-74. Epub 2008 Apr 4.

Bio-Mimetic Control Research Center, The Institute of Physical and Chemical Research, RIKEN, Nagoya, Japan.

Transcriptional autorepression has been thought to be one of the simplest control circuits to attenuate fluctuations in gene expression. Here, we explored the effect of autorepression on fluctuations from different noise sources. We theoretically represent the fluctuations in the copy number of proteins as the sum of several terms, each of which is related to a specific noise source and expressed as the product of the source-specific fluctuations under no autorepression (path gain) and the effect of autorepression on them (loop gain). Inspection of each term demonstrates the source-independent noise-attenuating effect of autorepression as well as its source-dependent efficiency. Our experiments using a synthetic autorepression module revealed that autorepression attenuates fluctuations of various noise compositions. These findings indicate that the noise-attenuating effect of autorepression is robust against variation in noise compositions. We also experimentally estimated the loop gain for mRNA noise, demonstrating that loop gains are measurable parameters. Decomposition of fluctuations followed by experimental estimation of path and loop gains would help us to understand the noise-related feature of design principles underlying loop-containing biological networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1529/biophysj.107.124677DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2479612PMC
August 2008

A mathematical model of respiratory and biothermal dynamics in brain hypothermia treatment.

IEEE Trans Biomed Eng 2008 Apr;55(4):1266-78

Bio-Mimetic Control Research Center, Institute of Physical and Chemical Research, Nagoya, Japan.

Brain hypothermia treatment (BHT) requires proper mechanical ventilation and therapeutic cooling. The cooling strategy for BHT has been mainly discussed in the literature while little information is available on the respiratory management. We first developed a mathematical model that integrates the respiratory and biothermal dynamics to discuss the simultaneous managements of mechanical ventilation and therapeutic cooling. The effect of temperature on the linear approximations of hemoglobin-oxygen dissociation, together with temperature dependency of metabolism, is introduced during modeling to combine the respiratory system with the biothermal system. By comparing its transient behavior with published data, the model is verified qualitatively and then quantitatively. Second, model-based simulation of the current respiratory management in BHT suggests reduction of minute ventilation in reference to cooled brain temperature to stabilize the states of blood and brain oxygenation. Lastly, the relationship between cooling temperature and minute ventilation is approximated by a linear first-order transfer function of static gain 0.61min(-1) degrees C(-1) and time constant 8.9 h, which is used to develop a feedforward control to tune the mechanical ventilator in concert with temperature regulation of the cooling blanket. Discussion of the model encourages further studies that provide direct evidence from clinical experiments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/TBME.2007.912400DOI Listing
April 2008

Reconstructing the single-cell-level behavior of a toggle switch from population-level measurements.

FEBS Lett 2008 Apr 4;582(7):1067-72. Epub 2008 Mar 4.

ERATO Aihara Complexity Modelling Project, JST, 45-18 Oyama, Shibuya-ku, Tokyo 151-0065, Japan.

Single-cell-level behaviors of cells are typically inferred from ensemble measurements. However, such inferences implicitly assume a biological version of ergodicity: the percentage of cells in a state is identical to the probability to find a cell in that state. While the ergodicity does not always hold, it has been rarely tested. Here, we reveal that the ergodicity does not necessarily hold even for simple toggle switches and that apparent stabilities of the switches are due to a balance between single-cell-level biased stabilities and growth rates differences. Therefore, verification of the ergodicity and reconstructing single-cell-level behaviors are crucial for understanding intracellular systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.febslet.2008.02.057DOI Listing
April 2008

Mathematical classification of regulatory logics for compound environmental changes.

J Theor Biol 2008 Mar 24;251(2):363-79. Epub 2007 Nov 24.

Bio-Mimetic Control Research Center, RIKEN, Shimo-shidami, Moriyamaku, Nagoya 463-0003, Japan.

This paper is concerned with biological regulatory mechanisms in response to the simultaneous occurrence of a huge number of environmental changes. The restricted resources of cells strictly limit the number of their regulatory methods; hence, cells must adopt, as compensation, special mechanisms to deal with the simultaneous occurrence of environmental changes. We hypothesize that cells use various control logics to integrate information about independent environmental changes related to a cell task and represent the resulting effects of the different ways of integration by logical functions. Using the notion of equivalence classes in set theory, we describe the mathematical classification of the effects into biologically unequivalent ones realized by different control logics. Our purely mathematical and systematic classification of logical functions reveals three elementary control logics with different biological relevance. To better understand their biological significance, we consider examples of biological systems that use these elementary control logics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtbi.2007.11.023DOI Listing
March 2008
-->