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| 中文名 | 2-氨基-4-(4-氟萘-1-基)-6-异丙基嘧啶盐酸盐 |
|---|---|
| 英文名 | 4-(4-Fluoronaphthalen-1-yl)-6-isopropylpyrimidin-2-amine hydrochloride |
| 英文别名 |
RS-127445 Hydrochloride
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride RS 127445 |
| 描述 | RS 127445 是一种选择性的 5-HT2B 受体拮抗剂,pKi 为 9.5。 |
|---|---|
| 相关类别 | |
| 靶点 |
5-HT1A Receptor:5.5 (pKi) 5-HT1B/D Receptor:<6 (pKi) 5-HT3 Receptor:<6 (pKi) 5-HT5 Receptor:<6 (pKi) 5-HT6 Receptor:<6 (pKi) 5-HT2A Receptor:6.3 (pKi) 5-HT2C Receptor:6.4 (pKi) 5-HT2B Receptor:9.5 (pKi) |
| 体外研究 | 发现RS-127445对5-HT2B受体具有纳摩尔亲和力(pKi = 9.5±0.1),并且与许多其他受体和离子通道结合位点相比,对该受体具有1,000倍的选择性。 RS-127445有效地置换CHO-K1细胞中表达的人重组5-HT2B受体的[3H] -5-HT。 RS-127445对5-HT2B受体的亲和力(pKi值)为9.5±0.1(n = 9)。 RS-127445对5-HT2B受体具有选择性,对人重组5-HT2A,5-HT2C,5-HT5,5-HT6和5-HT7受体的亲和力约为1000倍,大鼠中的5-HT1A受体脑膜,牛尾状核中的5-HT1B/D受体和兔血小板中的单胺摄取位点。 RS-127445有效阻断表达5-HT2B受体的HEK-293细胞中5-HT(10nM)引起的细胞内钙浓度的增加(pIC50为10.4±0.1)。在表达人重组5-HT2B受体的细胞中,RS-127445有效拮抗5-HT诱发的肌醇磷酸形成(pKB = 9.5±0.1)和5-HT诱发的细胞内钙增加(pIC10 = 10.4±0.1)。 RS-127445还可阻断5-HT诱发的大鼠离体胃底部收缩(pA2B = 9.5±1.1)和(±)α-甲基-5-HT介导的大鼠颈静脉松弛(pA2 = 9.9±0.3)[ 1]。 |
| 体内研究 | 在大鼠中,通过口服或腹膜内途径生物可利用的RS-127445的比例分别为14％和60％。腹膜内施用RS-127445(5mg/kg)产生的血浆浓度预计可使可接近的5-HT2B受体完全饱和至少4小时。通过口服,腹膜内和静脉内途径给予大鼠RS-127445(5mg/kg) 。在静脉内和腹膜内给药后(0.08小时)和通过口服给药途径给药后0.25小时测量的第一时间点发现最高浓度,迅速达到峰值血浆浓度。从等离子体中清除RS-127445,估计终末消除半衰期约为1.7小时。当通过口服和腹膜内途径给药时,RS-127445的生物利用度约为静脉内给药所得的生物利用度的14％和62％。大约60％的腹膜内剂量和14％的口服剂量RS-127445(5 mg/kg)是生物可利用的[1]。 RS-127445(1-30 mg/kg),剂量依赖性地减少粪便输出,在10和30 mg/kg(n = 6-11)时达到显着性。在血液和大脑中,> 98％的RS-127445是蛋白质结合的[2]。 |
| 激酶实验 | 使用磷酸盐缓冲盐水中的2mM EDTA收获表达人5-HT2A，5-HT2B或5-HT2C受体的CHO-K1细胞。通过四个均质化循环（Brinkman P10破碎剂）和离心（48,000×g，15分钟）制备细胞膜。如前所述，建立每个测定以实现稳态条件并优化特异性结合。对于5-HT2A受体，将来自1×10 6个细胞的膜与0.2nM [3H] - 酮色林在32℃下孵育60分钟。使用10μM甲基麦角酰胺测定非特异性结合。对于5-HT2B受体，将来自1.5×10 6个细胞的膜与0.2nM [3H] -5-HT在4℃温育120分钟。使用10μM5-HT测定非特异性结合。对于5-HT2C受体，将来自3×10 5个细胞的膜与0.5nM [3H] - 美舒麦白在32℃温育60分钟。使用10μM甲基麦角酰胺测定非特异性结合。通过已经用0.1％聚乙烯亚胺预处理的玻璃纤维过滤器（GF / B）进行真空过滤来终止测定。通过液体闪烁计数测定总和结合放射性。在这些测定中的每一种中实现大于90％的特异性结合。通过在超过100个额外的离子通道或受体结合位点测试化合物的亲和力，进一步检查RS-127445对5-HT2B受体的选择性。这些研究由Cerep使用标准方案[1]进行。 |
| 细胞实验 | 将表达人5-HT2B受体的HEK-293细胞与[3H] - 肌醇（1.67μCi/ mL）在162cm 2烧瓶中在37℃下在含有10％透析的胎牛血清的无肌醇的Ham's F12培养基中温育过夜。收获细胞，用磷酸盐缓冲盐水洗涤五次，并以约3×10 6个细胞/ mL的密度重悬于无肌醇的Ham's F12培养基中。 RS-127445（10μM）最初溶解于10％（v / v）DMSO和90％无肌醇的Ham's F12培养基中。随后用不含肌醇的Ham's F12培养基稀释。将5-HT溶于含有100mM LiCl和1mM抗坏血酸的无肌醇的Ham's F12培养基中。将RS-127445，载体或其他拮抗剂与240μL细胞悬浮液在37℃预温育20分钟。通过添加5-HT引发反应。 60分钟后，通过加入50μL冰冷的20％高氯酸终止反应，在冰水浴中冷却10分钟，然后用160μL1NKOH中和。每种样品在室温下用2ml 50mM Tris-HCl，pH 7.4稀释。将含水部分（2.2mL）转移到已用5ml蒸馏水洗涤的Dowex AG1X8柱（1ml，1：1，w / v）上。然后用18ml蒸馏水洗涤柱子，用3ml 1N HCl洗脱肌醇磷酸酯。使用Packard 1900CA分析仪[1]通过液体闪烁光谱测定洗脱的放射性。 |
| 动物实验 | 大鼠[1]使用雄性Sprague-Dawley大鼠（200g）。为了比较不同给药途径后RS-127445的血浆动力学，将90只大鼠分成三个治疗组，每组30只大鼠。向每只大鼠施用单剂量的RS-127445（5mg / kg）溶解（2.5mg / mL）的乙醇：丙二醇：水（10：50：40，v：v：v）。在给药后0.08,0.25,0.5,1,2,4,8和24小时，将大鼠麻醉并通过心脏穿刺收集血液样品。小鼠[2]使用成年雄性C57BL / 6J小鼠（25-30g）。 RS-127445（1nM-10μM，每组织单一浓度，15分钟接触时间）或载体（5或50μLDMSO）的作用表示为与四种前药的平均振幅相比的振幅变化百分比。 ，EFS后的收缩反应。使用双样本等方差t检验分析结果。 |
| 参考文献 |
| 分子式 | C17H17ClFN3 |
|---|---|
| 分子量 | 317.78800 |
| 精确质量 | 317.11000 |
| PSA | 51.80000 |
| LogP | 5.52470 |
| 储存条件 | 2-8℃ |
|
Section1. IDENTIFICATION OF THE SUBSTANCE/MIXTURE Product identifiers Product name: RS-127445 Hydrochloride CAS-No.: 199864-86-3 Relevant identified uses of the substance or mixture and uses advised against Identified uses: Laboratory chemicals, Manufacture of substances Section2. HAZARDS IDENTIFICATION Classification of the substance or mixture Classification according to Regulation (EC) No 1272/2008 [EU-GHS/CLP] Acute toxicity, Oral (Category 3) Skin irritation (Category 2) Eye irritation (Category 2) Specific target organ toxicity - single exposure (Category 3) Classification according to EU Directives 67/548/EEC or 1999/45/EC Toxic if swallowed. Irritating to eyes, respiratory system and skin. Label elements Labelling according Regulation (EC) No 1272/2008 [CLP] Pictogram Signal wordDanger Hazard statement(s) H301Toxic if swallowed. H315Causes skin irritation. H319Causes serious eye irritation. H335May cause respiratory irritation. Precautionary statement(s) P261Avoid breathing dust/ fume/ gas/ mist/ vapours/ spray. P301 + P310IF SWALLOWED: Immediately call a POISON CENTER or doctor/ physician. P305 + P351 + P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. Supplemental Hazardnone Statements According to European Directive 67/548/EEC as amended. Hazard symbol(s) R-phrase(s) R25Toxic if swallowed. R36Irritating to eyes. S-phrase(s) S26In case of contact with eyes, rinse immediately with plenty of water and seek medical advice. S45In case of accident or if you feel unwell, seek medical advice immediately (show the label where possible). Other hazards - none Section3. COMPOSITION/INFORMATION ON INGREDIENTS Substances Synonyms: 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine Hydrochloride Formula: C17H16FN3 · HCl Molecular Weight: 317,79 g/mol ComponentConcentration 2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride CAS-No.199864-86-3- Section4. FIRST AID MEASURES Description of first aid measures General advice Consult a physician. Show this safety data sheet to the doctor in attendance. If inhaled If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician. In case of skin contact Wash off with soap and plenty of water. Take victim immediately to hospital. Consult a physician. In case of eye contact Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician. If swallowed Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician. Most important symptoms and effects, both acute and delayed To the best of our knowledge, the chemical, physical, and toxicological properties have not been thoroughly investigated. Indication of any immediate medical attention and special treatment needed no data available Section5. FIRE-FIGHTING MEASURES Extinguishing media Suitable extinguishing media Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Special hazards arising from the substance or mixture Carbon oxides, nitrogen oxides (NOx), Hydrogen chloride gas, Hydrogen fluoride Advice for firefighters Wear self contained breathing apparatus for fire fighting if necessary. Further information no data available Section6. ACCIDENTAL RELEASE MEASURES Personal precautions, protective equipment and emergency procedures Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. Reference to other sections For disposal see section 13. Section7. HANDLING AND STORAGE Precautions for safe handling Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Conditions for safe storage, including any incompatibilities Store in cool place. Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 °C Specific end uses no data available Section8. EXPOSURE CONTROLS/PERSONAL PROTECTION Control parameters Components with workplace control parameters Exposure controls Appropriate engineering controls Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product. Personal protective equipment Eye/face protection Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). Skin protection Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. Body Protection Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. Respiratory protection Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Section9. PHYSICAL AND CHEMICAL PROPERTIES Information on basic physical and chemical properties a) AppearanceForm: solid b) Odourno data available c) Odour Thresholdno data available d) pHno data available e) Melting point/freezingMelting point/range: 156 - 158 °C point f) Initial boiling point and no data available boiling range g) Flash pointno data available h) Evaporation rateno data available i) Flammability (solid, gas) no data available j) Upper/lowerno data available flammability or explosive limits k) Vapour pressureno data available l) Vapour densityno data available m) Relative densityno data available n) Water solubilityno data available o) Partition coefficient: n- log Pow: 4,381 octanol/water p) Autoignitionno data available temperature q) Decompositionno data available temperature r) Viscosityno data available s) Explosive propertiesno data available t) Oxidizing propertiesno data available Other safety information no data available Section10. STABILITY AND REACTIVITY Reactivity no data available Chemical stability no data available Possibility of hazardous reactions no data available Conditions to avoid no data available Incompatible materials Strong oxidizing agents Hazardous decomposition products Other decomposition products - no data available Section11. TOXICOLOGICAL INFORMATION Information on toxicological effects Acute toxicity no data available Skin corrosion/irritation no data available Serious eye damage/eye irritation no data available Respiratory or skin sensitization no data available Germ cell mutagenicity no data available Carcinogenicity IARC:No component of this product present at levels greater than or equal to 0.1% is identified as probable, possible or confirmed human carcinogen by IARC. Reproductive toxicity no data available Specific target organ toxicity - single exposure Inhalation - May cause respiratory irritation. Specific target organ toxicity - repeated exposure no data available Aspiration hazard no data available Potential health effects Inhalation May be harmful if inhaled. Causes respiratory tract irritation. IngestionToxic if swallowed. SkinMay be harmful if absorbed through skin. Causes skin irritation. EyesCauses serious eye irritation. Signs and Symptoms of Exposure To the best of our knowledge, the chemical, physical, and toxicological properties have not been thoroughly investigated. Additional Information RTECS: Not available Section12. ECOLOGICAL INFORMATION Toxicity no data available Persistence and degradability no data available Bioaccumulative potential no data available Mobility in soil no data available Results of PBT and vPvB assessment no data available Other adverse effects no data available Section13. DISPOSAL CONSIDERATIONS Waste treatment methods Product Offer surplus and non-recyclable solutions to a licensed disposal company. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging Dispose of as unused product. Section14. TRANSPORT INFORMATION UN number ADR/RID: 2811IMDG: 2811IATA: 2811 UN proper shipping name ADR/RID: TOXIC SOLID, ORGANIC, N.O.S. (2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride) IMDG: TOXIC SOLID, ORGANIC, N.O.S. (2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride) IATA:Toxic solid, organic, n.o.s. (2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine hydrochloride) Transport hazard class(es) ADR/RID: 6.1IMDG: 6.1IATA: 6.1 Packaging group ADR/RID: IIIIMDG: IIIIATA: III Environmental hazards ADR/RID: noIMDG Marine pollutant: noIATA: no Special precautions for user no data available Section15. REGULATORY INFORMATION This safety datasheet complies with the requirements of Regulation (EC) No. 1907/2006. Safety, health and environmental regulations/legislation specific for the substance or mixture no data available Chemical Safety Assessment no data available Section16. OTHER INFORMATION Further information Copyright 2011 Co. License granted to make unlimited paper copies for internal use only. The above information is believed to be correct but does not purport to be all inclusive and shall be used only as a guide. The information in this document is based on the present state of our knowledge and is applicable to the product with regard to appropriate safety precautions. It does not represent any guarantee of the properties of the product. Co., shall not be held liable for any damage resulting from handling or from contact with the above product. See reverse side of invoice or packing slip for additional terms and conditions of sale. |
| 符号 |
GHS06 |
|---|---|
| 信号词 | Danger |
| 危害声明 | H301-H315-H319-H335 |
| 警示性声明 | P261-P301 + P310-P305 + P351 + P338 |
| 危险品运输编码 | UN 2811 6.1 / PGIII |
| 海关编码 | 2933599090 |
| 海关编码 | 2933599090 |
|---|---|
| 中文概述 | 2933599090. 其他结构上有嘧啶环的化合物(包括其他结构上有哌嗪环的化合物. 增值税率:17.0%. 退税率:13.0%. 监管条件:无. 最惠国关税:6.5%. 普通关税:20.0% |
| 申报要素 | 品名, 成分含量, 用途, 乌洛托品请注明外观, 6－己内酰胺请注明外观, 签约日期 |
| Summary | 2933599090. other compounds containing a pyrimidine ring (whether or not hydrogenated) or piperazine ring in the structure. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0% |