/In rats the/ product of final oxidation and main metabolite (up to 36% of applied dose /2-methoxy and thiadazole ring labeled (14)C/) was ...CO2. 2 ...Metabolites in urine were 2-methoxy-4-methylsulfinylmethyl-delta2-1,3,4-thiadiazolin-5-one (25%) and corresponding sulfone (7%). The methylthiomethyl derivative did not appear in significant amount. ...When labeled supracide was admin to lactating cow, analysis of milk, urine, and feces indicated that extensive degradation ...had occurred. No supracide or its oxygen analog was found in milk. ...In rumen ...degradation /to water sol metabolites/ ...was ...due to microbial activity. ...The locus l migratoria degraded the thiadiazole ring. Some CO2 and unidentified water-soluble metabolites were formed.
The most important metabolites observed /in rats following oral dose/ were 4-methylsulfinylmethyl- and 4-methylsulfonylmethyl-2-methoxy-1,3,4-thiadiazole-5-one. These metabolites originate by methylation and oxidation of the mercaptomethyl deriv liberated after hydrolysis of the p-s bond. Dimethyl phosphate, dimethyl phosphorothioate, methyl phosphate, inorganic phosphate and desmethyl gs-13005 were ...found in urine and/or feces. ...Cotton plants of delta-pine smoothleaf variety were grown and treated with (32)P labelled gs-13005 ...revealed ...desmethyl gs-13005, the oxon ...analog of gs-13005, dimethyl phosphorothioate, mono- and di-methyl phosphate, inorganic phosphate, unidentified metabolite and some unextracted radioactivity. ...In 5th instar tobacco budworms, gs-13005 was completely metabolized during 1st 4 hr. Small amount of thiolate analog and desmethyl analog formed ...but was depleted after 4 hr. Dimethyl phosphorothioate and dimethyl phosphate were major hydrolytic products. ...Other polar metabolites were ...observed.
5-Methoxy-1,3,4-thiadiazol-2-one is a metabolite of supracide ... . The first oxidative degradation reaction takes place with dithioate going to thiolate.
Details of the metabolism of the acidic group of methidathion have been explored using insecticide in which every carbon atom in this group was marked with (14)C. Up to 36% of the dose applied to rats was recovered as carbon dioxide. ... In another study in rats, it was shown that averages of 22.4, 25.8, and 17.7% of the applied dose were recovered as carbon dioxide when the 2-methoxy, carbonyl, and methylene carbons, respectively, of the acidic groups were labeled with (14)C. Dimethyl phosphate (33.6%) and dimethyl phosphorothioate (24.2%) were the main urinary metabolites of methidathion, but 11.1% was recovered during the first 48 hours as desmethyl methidathion. Almost 80% of intraperitoneal doses of (32)P methidathion was excreted in 48 hr, including 7.1% in the feces.
Metabolism of organophosphates occurs principally by oxidation, by hydrolysis via esterases and by reaction with glutathione. Demethylation and glucuronidation may also occur. Oxidation of organophosphorus pesticides may result in moderately toxic products. In general, phosphorothioates are not directly toxic but require oxidative metabolism to the proximal toxin. The glutathione transferase reactions produce products that are, in most cases, of low toxicity. Paraoxonase (PON1) is a key enzyme in the metabolism of organophosphates. PON1 can inactivate some organophosphates through hydrolysis. PON1 hydrolyzes the active metabolites in several organophosphates insecticides as well as, nerve agents such as soman, sarin, and VX. The presence of PON1 polymorphisms causes there to be different enzyme levels and catalytic efficiency of this esterase, which in turn suggests that different individuals may be more susceptible to the toxic effect of organophosphate exposure.
Methidathion is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
来源:Toxin and Toxin Target Database (T3DB)
毒理性
致癌性证据
癌症分类：C组可能的人类致癌物
Cancer Classification: Group C Possible Human Carcinogen
CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Increased incidence of liver adenomas, carcinomas, and combined adenomas and carcinomas in male mice. There was no shortening of time to tumor. Short-term tests and structure/activity study were not supportive of a higher classification. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
对人类不具有致癌性（未被国际癌症研究机构IARC列名）。
No indication of carcinogenicity to humans (not listed by IARC).
来源:Toxin and Toxin Target Database (T3DB)
毒理性
健康影响
急性接触胆碱酯酶抑制剂可能会导致胆碱能危象，表现为严重的恶心/呕吐、流涎、出汗、心动过缓、低血压、崩溃和抽搐。肌肉无力可能性增加，如果呼吸肌受到影响，可能会导致死亡。在运动神经积累的乙酰胆碱会导致神经肌肉接头处尼古丁受体的过度刺激。当这种情况发生时，可以看到肌肉无力、疲劳、肌肉痉挛、肌束震颤和麻痹的症状。当自主神经节积累乙酰胆碱时，这会导致交感系统中尼古丁受体的过度刺激。与此相关的症状包括高血压和低血糖。由于乙酰胆碱积累，中枢神经系统中尼古丁乙酰胆碱受体的过度刺激会导致焦虑、头痛、抽搐、共济失调、呼吸和循环抑制、震颤、全身无力，甚至可能昏迷。当由于乙酰胆碱过量而在毒蕈碱乙酰胆碱受体上出现毒蕈碱过度刺激时，可能会出现视力障碍、胸部紧绷、由于支气管收缩引起的喘息、支气管分泌物增加、唾液分泌增加、流泪、出汗、肠蠕动和排尿的症状。对于男性和女性的生育、生长和发育，某些生殖效应与有机磷农药暴露有特异性关联。关于生殖效应的大多数研究都是在农村地区使用农药和杀虫剂的农民中进行的。在女性中，月经周期紊乱、怀孕时间延长、自然流产、死产以及后代的一些发育效应与有机磷农药暴露有关。产前暴露与胎儿生长和发育受损有关。神经毒性效应也与有机磷农药中毒有关，在人类中引起四种神经毒性效应：胆碱能综合症、中间综合症、有机磷诱导的迟发性多发性神经病（OPIDP）和慢性有机磷诱导的神经精神障碍（COPIND）。这些综合症在急性 and 慢性暴露于有机磷农药后出现。
Acute exposure to cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Accumulation of ACh at motor nerves causes overstimulation of nicotinic expression at the neuromuscular junction. When this occurs symptoms such as muscle weakness, fatigue, muscle cramps, fasciculation, and paralysis can be seen. When there is an accumulation of ACh at autonomic ganglia this causes overstimulation of nicotinic expression in the sympathetic system. Symptoms associated with this are hypertension, and hypoglycemia. Overstimulation of nicotinic acetylcholine receptors in the central nervous system, due to accumulation of ACh, results in anxiety, headache, convulsions, ataxia, depression of respiration and circulation, tremor, general weakness, and potentially coma. When there is expression of muscarinic overstimulation due to excess acetylcholine at muscarinic acetylcholine receptors symptoms of visual disturbances, tightness in chest, wheezing due to bronchoconstriction, increased bronchial secretions, increased salivation, lacrimation, sweating, peristalsis, and urination can occur. Certain reproductive effects in fertility, growth, and development for males and females have been linked specifically to organophosphate pesticide exposure. Most of the research on reproductive effects has been conducted on farmers working with pesticides and insecticdes in rural areas. In females menstrual cycle disturbances, longer pregnancies, spontaneous abortions, stillbirths, and some developmental effects in offspring have been linked to organophosphate pesticide exposure. Prenatal exposure has been linked to impaired fetal growth and development. Neurotoxic effects have also been linked to poisoning with OP pesticides causing four neurotoxic effects in humans: cholinergic syndrome, intermediate syndrome, organophosphate-induced delayed polyneuropathy (OPIDP), and chronic organophosphate-induced neuropsychiatric disorder (COPIND). These syndromes result after acute and chronic exposure to OP pesticides.
Male and female CFI mice were treated dermally with (14)C-radiolabelled methidathion in the carbonyl carbon of the thiadiazole ring in acetone solution or formulated in petroleum hydrocarbon with emulsifier (the ratio of active ingredient to petroleum hydrocarbon to emulsifier was 6:10:1). The actual dermal dose was stated to be 12 mg/kg bw. The test solutions for both sexes were well absorbed through the skin as measured over a 72-hr period, with residual radioactivity on the skin in the acetone group of 0.47-0.67% and in the formulated product of 0.35-1.27% of the dose. The highest concentrations of radioactivity were recovered in the expired CO2 (50.85-64.1%) and urine (14.48-23.47%). Radioactivity found in tissues (0.3-0.7%) and blood (0.03-0.21%) was minimal. Total recovery represented 83-94% of the administered dose. The half-lives for the testing solutions on the skin were calculated for the acetone group to be 9.1 and 10.5 hr for males and females, and for the formulated group to be 10.4 and 10.9 hr for males and females, respectively. Blood and tissue levels appeared to plateau approximately 4 hr post-dosing, with tissue levels rarely exceeding 4 ppm.
Oral doses /in rats/ of three differently labeled forms ...were rapidly excreted in urine (up to 45%) and expired air (up to 36%). 24 hr after daily dosing ...for 10 days, <2% remained in tissues examined, and none after 48 hr. The lactating goat excreted around 1% of dose ...into milk in 72 hr.
Rats were dosed orally .../studies/ indicated complete absorption .../labeled/gs-13005 was distributed rapidly but radioactive content of all organs was below limit of detection 48 hr after dosage except for traces in muscles. Most ...was excreted in urine as polar metabolites... .
...Oral dose of (14)C-carbonyl supracide ...was ...degraded by cow. 16-51% of (14)C was thought to have been excreted in expired air, 43% in urine, 4% in feces and 1% in milk. Serum levels of (14)C peaked within 5 hr of dosing.
ArbeitenüberPhosphorsäure-andThiophosphorsäureestermit einem heterocyclischen Subitententen。8. Mitteilung。达斯史陶比尔-Verfahren，EINE Eintopf-Kondensation冯Thiophosphorverbindungen（，XO，S），Aldehyden UND Heterocyclen（MIT苏拉NH-GRUPPE）†
Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes
摘要：
Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alpha K(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
[EN] BICYCLYL-SUBSTITUTED ISOTHIAZOLINE COMPOUNDS<br/>[FR] COMPOSÉS ISOTHIAZOLINE SUBSTITUÉS PAR UN BICYCLYLE
申请人：BASF SE
公开号：WO2014206910A1
公开（公告）日：2014-12-31
The present invention relates to bicyclyl-substituted isothiazoline compounds of formula (I) wherein the variables are as defined in the claims and description. The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
The present invention relates to azoline compounds of formula (I) wherein A, B1, B2, B3, G1, G2, X1, R1, R3a, R3b, Rg1 and Rg2 are as defined in the claims and the description. The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
