Identification of a novel 2-pyridyl-benzensulfonamide derivative, RQ-00203078, as a selective and orally active TRPM8 antagonist.

A novel series of 2-pyridyl-benzensulfonamide derivatives have been identified as selective and orally active TRPM8 antagonists via high throughput screening (HTS). Exploration of the structure-activity relationships of compound 1 has led to the identification of RQ-00203078 (compound 36) as a highly selective, potent and orally available TRPM8 antagonist. RQ-00203078 demonstrated excellent in vivo activity in a dose dependent manner with an ED50 value of 0.

Effects of 5-HT2B, 5-HT3 and 5-HT4 receptor antagonists on gastrointestinal motor activity in dogs.

Aim: To study the effects of 5-hydroxytryptamine (5-HT) receptor antagonists on normal colonic motor activity in conscious dogs.

Methods: Colonic motor activity was recorded using a strain gauge force transducer in 5 dogs before and after 5-HT2B, 5-HT3 and 5-HT4 receptor antagonist administration. The force transducers were implanted on the serosal surfaces of the gastric antrum, terminal ileum, ileocecal sphincter and colon.

Polychlorinated dibenzo-p-dioxins, dibenzofurans, and dioxin-like polychlorinated biphenyls in rice straw smoke and their origins in Japan.

Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL-PCBs) contained in the smoke generated from rice straw burning in post-harvest paddy fields in Japan were analyzed to determine their congener profiles. Both the apportionment of toxic equivalent (TEQ) by using indicative congeners and the comparison of the homolog profiles showed that the PCDDs/PCDFs/DL-PCBs present in the rice-straw smoke were greatly influenced by those present as impurities in pentachlorophenol (PCP) and chlornitrofen (CNP, 4-nitrophenyl-2,4,6-trichlorophenyl ether) formulations that had been widely used as herbicides in paddy fields in Japan. Further, in order to investigate the effects of paddy-field soil on the PCDDs/PCDFs/DL-PCBs present in rice-straw smoke, PCDD/PCDF/DL-PCB homolog profiles of rice straw, rice-straw smoke and paddy-field soil were compared.

Seasonal change of PCDDs/PCDFs/DL-PCBs in the water of Ayase River, Japan: pollution sources and their contributions to TEQ.

In Japan, Ayase River is one of the most polluted rivers by PCDDs, PCDFs and dioxin-like PCBs, which are referred to as dioxins in this paper. The water samples of the river were collected once per month for a year, and dioxins were analyzed to examine the dioxin sources and their contributions to toxic equivalent (TEQ). The WHO-2006 TEQs ranged from 0.

A simplified determination method of dioxin toxic equivalent (TEQ) by single GC/MS measurement of five indicative congeners.

Here, we proposed a simplified determination method for dioxin (polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls (PCBs)) toxic equivalency (TEQ; based on the World Health Organization-2006 toxicity equivalent factor) in environmental samples collected in Japan. This method has estimated the total TEQ from the concentrations of only five indicative congeners, namely, 2,3,4,7,8-pentachlorodibenzofuran; 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin; 1,2,3,7,8-pentachlorodibenzo-p-dioxin; and PCBs of IUPAC Nos. #126 and #105, which were obtained from a single GC/MS measurement using a combination of columns of 10-meter-long DB-5ms (injector side) and 20-meter-long DB-17ms (detector side).

Apportionment of TEQs from four major dioxin sources in Japan on the basis of five indicative congeners.

The major sources of dioxins (polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like polychlorinated biphenyls (DL-PCBs)) in the environment in Japan have been considered to be combustion by-products, pentachlorophenol (PCP) formulations, chlornitrofen (CNP, 4-nitrophenyl-2,4,6-trichlorophenyl ether) formulations, and PCB products. Data on PCDDs, PCDFs and DL-PCBs from the four sources were analyzed, and indicative congeners whose concentrations were highly correlated with WHO-2006 toxic equivalencies (TEQs) were identified for each source sample. The indicative congeners for combustion by-products, PCP formulations, and CNP formulations were 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,7,8-pentachlorodibenzo-p-dioxin, respectively; for PCB products, the indicative congeners were IUPAC Nos.

Foaming control by automatic carbon source adjustment using an ORP profile in sequencing batch reactors for enhanced nitrogen removal in swine wastewater treatment.

Incomplete denitrification and ammonia accumulation were found to cause proliferation of filamentous microorganisms in sequencing batch reactors (SBRs) for swine wastewater treatment. Foaming was observed in response to the accumulation of 115.2 and 12.

Mass balance study of nonylphenol ethoxylates and their metabolites in an urban river contaminated by nonylphenol.

In previous studies, an urban river called Kamo River was found to be polluted with nonylphenol (NP) by a rubber product manufacturing factory. To determine the contribution of the factory effluent to the river pollution, a mass balance study was conducted for NP, nonylphenol ethoxylates (NPnEOs, n = 1-15), and nonylphenol carboxylates (NPmECs, m = 1-10) in the waters of the river and its 10 inflow channels. The total concentration of nonylphenolic compounds (T-NPCs) in the river water was 4.

Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: classification criteria and application to drug candidates.

We have previously demonstrated that the phototoxic potential of chemicals could be partly predicted by the determination of reactive oxygen species (ROS) from photo-irradiated compounds. In this study, ROS assay strategy was applied to 39 marketed drugs and 210 drug candidates in order to establish provisional classification criteria for risk assessment of drug-induced phototoxicity. The photosensitizing properties of 39 model compounds consisting of phototoxic and non-phototoxic chemicals, as well as ca.

Seasonal changes in nonylphenol ethoxylates and their metabolites in water and sediment of urban river polluted by nonylphenol.

The concentrations of nonylphenol (NP), nonylphenol ethoxylates (NPnEOs: n = 1-15) and nonylphenoxy acetic acids (NPmECs: m = 1-10) in river water and sediment were determined seasonally at four sampling sites in the Kamo River, which is a typical urban river and was already known to be polluted by NP. In the water, the concentrations of NP, NPnEOs and NPmECs ranged from 0.13 to 3.

Optimization of imidazole 5-lipoxygenase inhibitors and selection and synthesis of a development candidate.

Structural modification of imidazole 5-lipoxygenase (5-LO) inhibitors for optimizing inhibitory potency, pharmacokinetic behavior and toxicity (ocular) profile led to 4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (6) with no observable ocular toxicity. The orally active and safe imidazole 5-LO inhibitor 6 was selected as a clinical candidate and advanced to clinical studies. An improved synthesis of 6 is also discussed.

Preparation of optically pure propargylic and allylic alcohols from 2-(trimethylsilyl)vinyl sulfoxides as a chiral ethynyl anion synthon: computational studies on elimination reaction of 2-(trimethylsilyl)vinyl sulfoxides.

The reaction of the alpha-carbanion derived from (trimethylsilyl)vinyl sulfoxides with aldehydes afforded a diastereomeric mixture of the products. Each diastereomer was subjected to specific elimination reactions to give optically pure propargylic, trimethylsilylated propargylic, and allylic alcohols. Acceleration of the sulfenic acid-elimination from the beta-silylvinyl sulfoxide was demonstrated by the ab initio calculation to be ascribed mainly to the beta-effect of the silyl group.