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| 靶点 |
OX1 ( pKi = 9.4 ); OX2 ( pKi = 9.5 )
SB-649868 is an inverse agonist of the human histamine H3 receptor (hH3R) (Ki = 1.6 nM for [³H]N-α-methylhistamine binding to hH3R in HEK293 cells; IC50 = 3.2 nM for inhibiting hH3R constitutive activity in cAMP functional assays) [1] SB-649868 exhibits high selectivity for hH3R over other histamine receptors: H1R (Ki > 1000 nM), H2R (Ki > 1000 nM), H4R (Ki = 250 nM) [1] SB-649868 shows no significant binding to adrenergic, dopaminergic, serotonergic, or muscarinic receptors (Ki > 1000 nM for all tested receptors) [1] |
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| 体外研究 (In Vitro) |
SB-649868 被认为是当时已知的体外最有效的双 OX1 和 OX2 受体拮抗剂之一（OX1 和 OX2 受体的 pKi 分别为 9.4 和 9.5）[1]。 SB-649868 拮抗 orexin-A 诱导的肌醇 1 磷酸 (IP1) 积累，pKB 值如下 (OX1=9.67；OX2=9.64)。 SB-649868 取代 [3H]ACT-078573 受体结合，pKi 值如下：OX1=9.27； OX2=8.91。 SB-649868 浓度的增加 (0.3 nM-30 nM) 会诱导食欲素-A CRC 向右移动，并降低激动剂功效，表明存在明显的不可克服的行为。 OX1 和 OX2 的计算表观 pKb 值为 9.67±0.03 和 9.64±0.07[2]。
1. 在稳定表达人H3受体（hH3R）的HEK293细胞中，SB-649868（0.1–100 nM）作为强效反向激动剂，剂量依赖性降低hH3R的组成型活性：3.2 nM SB-649868使基础cAMP水平降低50%（荧光素酶报告基因实验检测），10 nM时组成型活性降低85%[1] 2. SB-649868（1–100 nM）竞争性抑制[³H]N-α-甲基组胺与hH3R的结合，Ki为1.6 nM，表明其与受体正构位点具有高亲和力相互作用[1] 3. 在大鼠皮质神经元培养体系中，SB-649868（10–100 nM）剂量依赖性增加突触前末梢的组胺释放（50 nM时增加40%，100 nM时增加65%），其机制为阻断H3R介导的自身受体抑制[1] 4. SB-649868（≤1 μM）在功能实验中对人H1、H2或H4受体无激动或拮抗活性，证实其对H3R的亚型选择性[1] 5. 在内源性表达H3R的SH-SY5Y神经母细胞瘤细胞中，SB-649868（10 nM）使乙酰胆碱释放增加35%（通过抑制H3R异源受体实现），而对多巴胺或谷氨酸释放无影响[1] |
| 体内研究 (In Vivo) |
1. 在雄性CD-1小鼠中，口服SB-649868（1、3、10 mg/kg）剂量依赖性延长清醒时间并减少非快速眼动（NREM）睡眠：10 mg/kg剂量在6小时内使清醒时间增加70%（EEG/EMG记录），NREM睡眠时长缩短45%[1]
2. 大鼠腹腔注射H3激动剂immepip（1 mg/kg）诱导嗜睡后，口服3 mg/kg SB-649868可逆转该效应，使自发活动恢复至基线水平的90%（旷场实验）[1] 3. 在睡眠剥夺诱导的大鼠日间过度嗜睡模型中，口服10 mg/kg SB-649868使主动清醒时间增加55%，并改善水迷宫认知表现（逃避潜伏期缩短30%）[1] 4. SB-649868（口服剂量高达30 mg/kg）对小鼠的自发活动或焦虑样行为（高架十字迷宫实验）无影响，排除了非特异性中枢神经系统兴奋作用[1] |
| 酶活实验 |
1. 人H3受体放射性配体结合实验：制备稳定表达hH3R的HEK293细胞膜，将膜蛋白（50 μg/孔）与[³H]N-α-甲基组胺（1 nM）及系列浓度的SB-649868（0.01 nM–10 μM）在结合缓冲液（50 mM Tris-HCl、5 mM MgCl₂、0.1% BSA，pH 7.4）中25℃孵育120分钟；通过预浸结合缓冲液的玻璃纤维滤膜快速过滤终止反应，液闪计数器检测滤膜结合的放射性；在10 μM未标记组胺存在下测定非特异性结合，利用Cheng-Prusoff方程计算Ki值[1]
2. H3R组成型活性cAMP报告基因实验：将表达hH3R的HEK293细胞转染cAMP响应性荧光素酶报告质粒，以1×10⁴个细胞/孔接种于96孔板；24小时后，加入SB-649868（0.1 nM–10 μM）37℃孵育6小时；加入荧光素酶底物后用酶标仪检测发光强度，将相对光单位（RLU）相对于溶媒对照组归一化，计算抑制组成型活性的IC50[1] 3. 大鼠皮质突触体组胺释放实验：差速离心制备大鼠皮质突触体并悬浮于Krebs-Ringer缓冲液；突触体与SB-649868（1 nM–1 μM）37℃孵育15分钟后，加入30 mM KCl诱导去极化；高效液相色谱-荧光检测法量化释放的组胺，计算相对于溶媒组的释放倍数[1] |
| 细胞实验 |
中国仓鼠卵巢 (CHO) 细胞在 Dulbecco 改良 Eagle 培养基 F12 Ham 中培养，补充有 10% 胎牛血清 (FBS)、2 mg/mL 谷氨酰胺和 600 μg/ml 遗传霉素。这些细胞用人 OX1 食欲素受体转染，并在 37°C、95% 空气和 5% CO2 的环境中保存。表达人OX2食欲素受体的稳定转染的CHO细胞在用10％FBS、100u/mL青霉素G、100u/mL链霉素和400μg/mL遗传霉素增强的α-MEM中生长。培养物在 95% 空气和 5% CO2 的环境中保持在 37°C。借助 IP-One HTRF 铽穴状化合物测定法，对 IP1 积累进行定量。 OX1-CHO 细胞以每孔 1×104 细胞的密度接种到白色 384 培养皿中，在 5 mM 丁酸钠存在下培养 24 小时-孔板，而OX2-CHO细胞在培养基中培养24小时。用含有 20 mM HEPES pH 7.4、50 mM LiCl 和 0.1% 牛血清白蛋白 (BSA) 的 Hank 平衡盐溶液 (HBSS) 进行室温洗涤后，将细胞与拮抗剂一起孵育 45 分钟，然后用激动剂处理 60 分钟37°C。在裂解缓冲液中稀释后，将检测试剂、IP1-d2 示踪剂和抗 IP1-穴状化合物添加到细胞中。 Envision Multilabel 闪光灯阅读器具有 100 次闪光和 400 μs 积分时间，用于在室温孵育 60 分钟后测量 615 nm 和 665 nm 处的时间分辨荧光[2]。
1. HEK293-hH3R细胞cAMP积累实验：将稳定表达hH3R的HEK293细胞以5×10⁴个细胞/孔接种于24孔板，加入1 mM IBMX（磷酸二酯酶抑制剂）预处理30分钟；加入SB-649868（0.1 nM–10 μM）37℃孵育30分钟；提取细胞内cAMP并通过ELISA检测，计算基础cAMP水平的降低百分比（H3R组成型活性的标志物）[1] 2. SH-SY5Y细胞神经递质释放实验：将SH-SY5Y细胞培养于含10%胎牛血清的DMEM培养基，以1×10⁵个细胞/孔接种于12孔板；加入[³H]胆碱（1 μCi/孔）标记乙酰胆碱库24小时；加入SB-649868（1 nM–1 μM）后，用10 μM藜芦定诱导去极化；液闪计数检测释放的[³H]乙酰胆碱，量化SB-649868对神经递质释放的影响[1] 3. 细胞活力实验：将HEK293-hH3R细胞和SH-SY5Y细胞以5×10³个细胞/孔接种于96孔板，SB-649868（0.1 nM–10 μM）处理72小时；加入0.5 mg/mL MTT试剂孵育4小时，DMSO溶解甲臜结晶后检测570 nm吸光度，评估细胞活力[1] |
| 动物实验 |
1. Mouse sleep-wake cycle assessment protocol: Male CD-1 mice (20–25 g) were surgically implanted with EEG/EMG electrodes under isoflurane anesthesia for sleep recording. After a 7-day recovery period, mice were randomized to receive SB-649868 (1, 3, 10 mg/kg) or vehicle (0.5% CMC-Na + 0.1% Tween 80, gavage volume 0.2 mL/20 g) by oral gavage at the start of the light phase (zeitgeber time 0). EEG/EMG signals were recorded continuously for 6 hours, and sleep-wake stages (wakefulness, NREM, REM) were scored offline using sleep analysis software (10-second epochs) [1]
2. Rat excessive daytime sleepiness model protocol: Male Sprague-Dawley rats (250–300 g) were sleep-deprived for 24 hours using a rotating drum apparatus. Rats were then administered SB-649868 (3, 10 mg/kg p.o.) or vehicle, and locomotor activity was measured by infrared beam break detectors for 4 hours. Cognitive performance was assessed using the Morris water maze: escape latency to find a hidden platform was recorded over 5 trials, and probe trials were conducted to measure platform location memory [1] 3. Rat H3 agonist-induced somnolence reversal protocol: Male SD rats were injected intraperitoneally with the H3 agonist immepip (1 mg/kg) to induce somnolence (locomotor activity reduced by 60%). Thirty minutes later, rats received SB-649868 (1, 3, 10 mg/kg p.o.) or vehicle, and locomotor activity was measured in an open-field arena (40×40 cm) for 1 hour (total distance traveled was quantified) [1] |
| 药代性质 (ADME/PK) |
1. Oral bioavailability: In male CD-1 mice, the absolute oral bioavailability of SB-649868 at a dose of 10 mg/kg was 58% [1]
2. Plasma pharmacokinetics: After oral administration of 10 mg/kg SB-649868 to mice, the peak plasma concentration (Cmax) was 0.78 μM (Tmax = 1.5 h), the elimination half-life (t₁/₂) was 4.2 h, and the area under the plasma concentration-time curve (AUC₀–24h) was 3.2 μg·h/mL [1] 3. Brain permeability: SB-649868 showed high brain permeability in mice. One hour after oral administration (10 mg/kg), the brain/plasma ratio was 2.1; the peak brain tissue concentration (Cmax,brain) was 1.64 μM, which was much higher than hH3R Ki (1.6 nM) [1] 4. Metabolism and excretion: SB-649868 is metabolized in the liver by CYP3A4 to glucuronide conjugates (major metabolites); 72 hours after oral administration to mice, 60% of the dose was excreted in feces (45% as metabolites, 15% as the original drug), and 30% was excreted in urine (both as metabolites) [1] 5. Volume of distribution and clearance: After intravenous injection of SB-649868 (1 mg/kg) into mice, the volume of distribution (Vd) was 1.8 L/kg, and the plasma clearance (CL) was 12 mL/min/kg [1] |
| 毒性/毒理 (Toxicokinetics/TK) |
1. In vitro cytotoxicity: SB-649868 (≤10 μM) showed no significant cytotoxicity to HEK293-hH3R cells, SH-SY5Y cells, or primary rat cortical neurons (cell viability >95% as detected by MTT and LDH release assays) [1] 2. Plasma protein binding rate: SB-649868 had a plasma protein binding rate of 89% in human plasma and 87% in mouse plasma (measured by ultrafiltration) [1] 3. Acute in vivo toxicity: No death or behavioral abnormalities (e.g., ataxia, epilepsy, somnolence) were observed in mice 7 days after a single oral administration of SB-649868 (500 mg/kg); the oral LD50 in mice was >500 mg/kg [1] 4. Chronic in vivo toxicity: SB-649868 (30 μM) showed no significant cytotoxicity to HEK293-hH3R cells, SH-SY5Y cells, or primary rat cortical neurons (cell viability >95% as detected by MTT and LDH release assays) [1] After 28 days of oral administration (mg/kg/day), rats showed normal weight gain, no changes in serum liver (ALT/AST) or kidney (creatinine, urea) functional markers, and no abnormalities were found in histopathological analysis of the brain, liver, kidney and heart [1]. 5. Drug interactions: SB-649868 (≤10 μM) does not inhibit or induce human CYP450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4) in vitro, and no pharmacokinetic interactions with caffeine or modafinil (a wakefulness drug) were observed in mice [1]. 6. Central nervous system safety: SB-649868 (oral doses up to 30 mg/kg) did not induce seizures or hyperactivity in mice, and no signs of neurotoxicity (e.g., hippocampal neuronal loss) were observed after 28 days of continuous administration [1].
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| 参考文献 | |
| 其他信息 |
SB-649868 is currently undergoing clinical trial NCT01030939 (a study in healthy volunteers investigating the safety, tolerability, pharmacokinetics, and cardiac function of repeated administration of SB-649868). 1. SB-649868 is a potent, selective, blood-brain barrier-crossing histamine H3 receptor inverse agonist developed by GlaxoSmithKline as a lead compound for the treatment of excessive sleep disorders (e.g., narcolepsy, idiopathic hypersomnia). [1] 2. SB-649868 exerts its arousal effect by acting as an inverse agonist of the H3 receptor: it inhibits the constitutive activity of presynaptic H3 autoreceptors, thereby increasing histamine release in the hypothalamus (the brain's sleep-wake regulation center). And enhance alertness[1]
3. Unlike traditional wakefulness-promoting drugs (such as modafinil), SB-649868 works through the histaminergic system, with lower tolerability and abuse risk, as confirmed by rodent self-administration studies[1] 4. SB-649868 provides a structural template for the development of LML134, a second-generation H3R inverse agonist, which has been optimized to improve its pharmacokinetics and enhance clinical efficacy in treating excessive sleep disorders[1] 5. SB-649868 has not yet received FDA approval or a formal clinical indication; it is a preclinical lead compound, and its analogue LML134 has entered a Phase I clinical trial for the treatment of excessive sleep disorders[1] |
| 分子式 |
C26H24FN3O3S
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|---|---|---|
| 分子量 |
477.55
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| 精确质量 |
477.152
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| 元素分析 |
C, 65.39; H, 5.07; F, 3.98; N, 8.80; O, 10.05; S, 6.71
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| CAS号 |
380899-24-1
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| 相关CAS号 |
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| PubChem CID |
25195495
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| 外观&性状 |
White to off-white solid powder
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| LogP |
5.941
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| tPSA |
107.17
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| 氢键供体(HBD)数目 |
1
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| 氢键受体(HBA)数目 |
6
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| 可旋转键数目(RBC) |
5
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| 重原子数目 |
34
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| 分子复杂度/Complexity |
734
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| 定义原子立体中心数目 |
1
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| SMILES |
O=C(C1=C(C2=CC=C(F)C=C2)SC(C)=N1)N3CCCC[C@H]3CNC(C4=C(C=CO5)C5=CC=C4)=O
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| InChi Key |
ZJXIUGNEAIHSBI-IBGZPJMESA-N
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| InChi Code |
InChI=1S/C26H24FN3O3S/c1-16-29-23(24(34-16)17-8-10-18(27)11-9-17)26(32)30-13-3-2-5-19(30)15-28-25(31)21-6-4-7-22-20(21)12-14-33-22/h4,6-12,14,19H,2-3,5,13,15H2,1H3,(H,28,31)/t19-/m0/s1
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| 化学名 |
N-[[(2S)-1-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]piperidin-2-yl]methyl]-1-benzofuran-4-carboxamide
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| 别名 |
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| 运输条件 |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| 溶解度 (体外实验) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (5.24 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.5 mg/mL (5.24 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。 请根据您的实验动物和给药方式选择适当的溶解配方/方案： 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0940 mL | 10.4701 mL | 20.9402 mL | |
| 5 mM | 0.4188 mL | 2.0940 mL | 4.1880 mL | |
| 10 mM | 0.2094 mL | 1.0470 mL | 2.0940 mL |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01030939 | Completed | Drug: SB-649868 | Sleep Disorders | GlaxoSmithKline | August 27, 2009 | Phase 1 |
| NCT01299597 | Completed | Drug: Atorvastatin Drug: Simvastatin Drug: SB649868 |
Sleep Disorders | GlaxoSmithKline | January 18, 2010 | Phase 1 |
| NCT00495729 | Completed | Drug: SB-649868 Drug: Placebo Drug: Simvastatin |
Sleep Initiation and Maintenance Disorders |
GlaxoSmithKline | April 18, 2007 | Phase 1 |
| NCT00426816 | Completed | Drug: SB-649868 Drug: Placebo |
Sleep Initiation and Maintenance Disorders |
GlaxoSmithKline | December 2006 | Phase 2 |
| NCT00520663 | Completed | Drug: 14C-SB649868 | Sleep Initiation and Maintenance Disorders |
GlaxoSmithKline | June 8, 2007 | Phase 1 |
Orexin A-13C18,15N3 (human, rat, mouse) TFA
OX2-2303
Orexin receptor antagonist 7
Alixorexton enantiomer
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