艾代拉利司 | 870281-82-6

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 中文名称: 艾代拉利司
• 中文别名: 艾代拉里斯；5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)-喹唑啉酮；艾德拉尼；5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]-4(3H)喹唑啉
• 英文名称: idelalisib
• 英文别名: CAL-101；GS-1101；5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone；zydelig；5-fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]quinazolin-4-one
• CAS: 870281-82-6
• 化学式: C₂₂H₁₈FN₇O
• 分子量: 415.43
• InChiKey: IFSDAJWBUCMOAH-HNNXBMFYSA-N

物化性质

• 熔点：
  250-252oC
• 沸点：
  733.4±70.0 °C(Predicted)
• 密度：
  1.47
• 溶解度：
  溶于DMSO(>25mg/ml)
• 颜色/状态：
  White to off-white powder
• 蒸汽压力：
  5.2X10-16 mm Hg at 25 °C (est)
• 稳定性/保质期：
  Stable if stored in accordance with information listed on the product insert.
• 分解：
  Hazardous Decomposition or Byproducts: carbon dioxide, carbon monoxide, nitrogen oxides.

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  99.2
• 氢给体数：
  2
• 氢受体数：
  7

ADMET

代谢

伊达利西布通过醛氧化酶和CYP3A代谢为其主要代谢物GS-563117，该代谢物对P110δ无效。伊达利西布还通过UGT1A4进行了少量的代谢。

Idelalisib is metabolized by aldehyde oxidase and CYP3A to its major metabolite GS-563117, which is inactive against P110δ. Idelalisib is also metabolized to a minor extent by UGT1A4.

来源:DrugBank

代谢

伊达拉利布，一种强效的磷脂酰肌醇-3-激酶δ（PI3Kd）抑制剂，主要通过醛氧化酶代谢形成GS-563117，其次通过细胞色素P450（CYP）3A和尿苷5'-二磷酸-葡萄糖醛酸基转移酶1A4。在体外，伊达拉利布抑制P-糖蛋白（P-gp）和有机阴离子转运多肽1B1和1B3，GS-563117是时间依赖性的CYP3A抑制剂。本研究纳入了24名健康受试者，评估了（1）伊达拉利布对地高辛（P-gp探针底物）、瑞舒伐他汀（乳腺癌耐药蛋白和OATP1B1/OATP1B3底物）和咪达唑仑（CYP3A底物）药代动力学（PK）的影响；（2）强诱导剂利福平对伊达拉利布PK的影响。治疗期间，最常见的临床不良事件（AEs）是头痛和发热。24名受试者中有5名出现3级转氨酶升高，且是可逆的。两名受试者在治疗完成后出现了严重的不良事件（3级发热和/或药物诱导的肝损伤）。伊达拉利布联合用药不影响地高辛和瑞舒伐他汀的PK。与伊达拉利布联合用药增加了咪达唑仑的血浆暴露量（分别为最大观察血浆浓度（Cmax）的138%和437%，从时间0外推到无穷大的血浆浓度-时间曲线下面积（AUCinf）），这与GS-563117在体外对CYP3A的抑制一致。利福平导致伊达拉利布（分别为Cmax和AUCinf的58%和75%）和GS-563117暴露量显著下降，表明在强烈诱导状态下CYP3A对伊达拉利布代谢的贡献增强。

Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kd) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf), respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.

来源:Hazardous Substances Data Bank (HSDB)

代谢

idelalisib超过84%与血浆蛋白结合。Idelalisib主要通过细胞色素P-450（CYP）同工酶3A和醛氧化酶代谢为其主要代谢物GS-563117；该药物仅通过尿苷二磷酸-葡萄糖醛酸转移酶（UGT）1A4.1进行少量代谢。GS-563117在体外对PI3Kdelta无效。

Idelalisib is more than 84% bound to plasma proteins. Idelalisib is metabolized to its major metabolite, GS-563117, principally by cytochrome P-450 (CYP) isoenzyme 3A and aldehyde oxidase; the drug is metabolized only to a minor extent by uridine diphosphate-glucuronosyl transferase (UGT) 1A4.1 GS-563117 is inactive against PI3Kdelta in vitro.

来源:Hazardous Substances Data Bank (HSDB)

代谢

伊达拉利布通过醛氧化酶和CYP3A代谢，同时还伴有UGT1A4的少量代谢。

Idelalisib is metabolized via aldehyde oxidase and CYP3A with additional minor metabolism by UGT1A4.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：依德利塞是一种白色至类白色的粉末。它用作抗肿瘤剂和酶抑制剂。它用于治疗复发性慢性淋巴细胞白血病、复发性滤泡性B细胞非霍奇金淋巴瘤和复发性小淋巴细胞淋巴瘤的患者。人体研究：依德利塞是PI3Kdelta

IDENTIFICATION AND USE: Idelalisib is a white to off-white powder. It is used as antineoplastic agent, and enzyme inhibitor. It is indicated for the treatment of patients with relapsed chronic lymphocytic leukemia, relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma. HUMAN STUDIES: Idelalisib is an inhibitor of PI3Kdelta kinase, which is expressed in normal and malignant B-cells. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability. Severe neutropenia has been reported in 31% of patients receiving idelalisib in clinical studies. Fatal cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have occurred in patients treated with the drug. Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with idelalisib monotherapy and 16% of patients treated with the drug in combinations. Fatal and serious intestinal perforation occurred in treated patients. Severe diarrhea or colitis occurred in 14% of patients treated with idelalisib monotherapy and 20% of patients treated with the drug in combinations. Fatal and serious pneumonitis occurred in patients treated with the drug. Fatal and/or serious infections occurred in 21% of patients treated with idelalisib monotherapy and 48% of patients treated with the drug in combinations. Idelalisib was not clastogenic in the in vitro chromosome aberration assay using human peripheral blood lymphocytes. ANIMAL STUDIES: Idelalisib was not carcinogenic in a 26-week study in transgenic mice when administered daily by oral gavage at doses up to 500 mg/kg/day in males and 1000 mg/kg/day in females. Idelalisib was not carcinogenic in a 2-year study in rats when administered daily by oral gavage. In an embryo-fetal development study in rats, pregnant animals receiving oral doses of idelalisib during the period of organogenesis (implantation to closure of the hard palate), embryo-fetal toxicities were observed at the mid- and high-doses that also resulted in maternal toxicity, based on reductions in maternal body weight gain. Adverse findings at idelalisib doses of 75 mg/kg/day included decreased fetal weights, external malformations (short tail), and skeletal variations (delayed ossification and/or unossification of the skull, vertebrae, and sternebrae). Additional findings were observed at 150 mg/kg/day dose of idelalisib and included urogenital blood loss, complete resorption, increased post-implantation loss, and malformations (vertebral agenesis with anury, hydrocephaly, and microphthalmia/anophthalmia). In a separate fertility study, treated female rats (25, 50, or 100 mg/kg/day of idelalisib) were mated with untreated males. There were no adverse effects on fertility parameters; however, there was a decrease in the number of live embryos at the high dose. Idelalisib did not induce mutations in the bacterial mutagenesis (Ames) assay. Idelalisib was genotoxic in males in the in vivo rat micronucleus study at a high dose of 2000 mg/kg.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

在伊达利西布联合利妥昔单抗治疗慢性淋巴细胞白血病（CLL）和淋巴瘤的临床试验中，治疗期间血清酶水平升高的发生率在25%至35%之间，超过正常上限（ULN）5倍的比例在5%至8%（与安慰剂和利妥昔单抗1%相比）。在接受伊达利西布单独治疗和联合利妥昔单抗治疗的病人中，报道了严重急性肝细胞损伤和急性肝衰竭的严重病例，但病例的临床特征并未详细描述。血清酶水平升高通常发生在开始治疗后的4至12周内，并且通常在暂时停止治疗后迅速解决。然而，在某些情况下，尽管停止治疗，血清转氨酶仍然很高，在这种情况下，皮质类固醇似乎有有益的效果。大多数在伊达利西布治疗中出现显著血清酶水平升高的患者，在再次挑战时迅速复发。然而，在接受皮质类固醇治疗的患者中，复发较少见且通常较轻，许多患者得以重新开始治疗。因此，伊达利西布是急性肝细胞损伤的常见原因，可能具有自身免疫成分。由于其许多严重的不良事件以及与其他药物相比疗效有限，伊达利西布并未广泛使用，其引起急性明显黄疸性肝损伤的潜力尚未得到很好的界定。 由于伊达利西布影响B细胞功能，它也可能能够诱导乙型肝炎的再激活，尽管在已发表的该药物试验中并未报告再激活。 临床明显肝损伤可能性评分：D（可能是临床明显肝损伤的原因）。

In clinical trials of idelalisib combined with rituximab in patients with CLL and lymphoma, the rates of serum enzyme elevations during therapy ranged from 25% to 35% and were above 5 times the ULN in 5% to 8% (compared to 1% with placebo and rituximab). Severe instances of severe acute hepatocellular injury and acute liver failure were reported in patients receiving idelalisib alone and with rituximab, but the clinical features of the cases were not be described in detail. Serum enzyme elevations typically arose within 4 to 12 weeks of starting therapy and usually resolved rapidly with temporary discontinuation. In some instances, however, serum aminotransferases remained high despite stopping therapy, and in this situation corticosteroids appeared to have a beneficial effect. Most patients who developed significant serum enzyme elevations with idelalisib had a rapid recurrence upon rechallenge. In patients receiving corticosteroids, however, recurrence was less common and generally mild, allowing for restarting of therapy in many patients. Thus, idelalisib is a frequent cause of acute hepatocellular injury which may have an autoimmune component. Because of its many serious adverse events and limited efficacy in comparison to other agents, idelalisib has not been widely used and it potential for causing acute clinically apparent liver injury with jaundice has not been well defined. Because, idelalisib affects B cell function, it may also be capable of inducing reactivation of hepatitis B, although in published trials of the agent, reactivation was not reported. Likelihood score: D (possible cause of clinically apparent liver injury).

来源:LiverTox

毒理性

• 在妊娠和哺乳期间的影响

母乳喂养期间使用的总结：目前没有关于母乳喂养期间使用idelalisib的临床信息。由于idelalisib超过84%与血浆蛋白结合，乳汁中的量可能较低。它有时与rituximab联合使用，这可能增加对婴儿的风险。制造商建议在idelalisib治疗期间及最后一次给药后至少1个月内停止哺乳。 ◉ 对哺乳婴儿的影响：截至修订日期，没有找到相关的已发布信息。 ◉ 对泌乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:No information is available on the clinical use of idelalisib during breastfeeding. Because idelalisib is more than 84% bound to plasma proteins, the amount in milk is likely to be low. It is sometimes given in combination with rituximab, which may increase the risk to the infant. The manufacturer recommends that breastfeeding be discontinued during idelalisib therapy and for at least 1 month after the last dose. ◉ Effects in Breastfed Infants:Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

毒理性

• 相互作用

使用Zydelig单药治疗的病人中有18%出现了致命和/或严重肝毒性，而使用Zydelig与利妥昔单抗或未经批准的联合疗法治疗的病人中有16%出现了这种情况。

Fatal and/or serious hepatotoxicity occurred in 18% of patients treated with Zydelig monotherapy and 16% of patients treated with Zydelig in combination with rituximab or with unapproved combination therapies.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

伊达拉利布，一种强效的磷脂酰肌醇-3-激酶δ（PI3Kd）抑制剂，主要通过醛氧化酶代谢形成GS-563117，其次通过细胞色素P450（CYP）3A和尿苷5'-二磷酸-葡萄糖醛酸基转移酶1A4。在体外，伊达拉利布抑制P-糖蛋白（P-gp）和有机阴离子转运多肽1B1和1B3，GS-563117是时间依赖性的CYP3A抑制剂。本研究纳入了24名健康受试者，评估了（1）伊达拉利布对地高辛（P-gp探针底物）、瑞舒伐他汀（乳腺癌耐药蛋白和OATP1B1/OATP1B3底物）以及咪达唑仑（CYP3A底物）药代动力学（PK）的影响；（2）强诱导剂利福平对伊达拉利布PK的影响。治疗期间，最常见的临床不良事件（AEs）是头痛和发热。24名受试者中有5名观察到3级转氨酶升高，且是可逆的。两名受试者在治疗完成后出现了严重的不良事件（3级发热和/或药物诱导的肝损伤）。伊达拉利布联合用药不影响地高辛和瑞舒伐他汀的PK。与伊达拉利布联合用药增加了咪达唑仑的血浆暴露量（分别为最大观察血浆浓度（Cmax）的138%和437%，从时间0外推到无穷大的血浆浓度-时间曲线下面积（AUCinf）），与体外GS-563117对CYP3A的抑制一致。利福平导致伊达拉利布（分别为Cmax和AUCinf的58%和75%）和GS-563117暴露量显著下降，表明在强烈诱导状态下，CYP3A对伊达拉利布代谢的贡献增强。

Idelalisib, a potent phosphatidylinositol-3-kinase delta (PI3Kd) inhibitor, is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by cytochrome P450 (CYP) 3A and uridine 5'-diphospho-glucuronosyltransferase 1A4. In vitro, idelalisib inhibits P-glycoprotein (P-gp) and organic anion transporting polypeptides 1B1 and 1B3, and GS-563117 is a time-dependent CYP3A inhibitor. This study enrolled 24 healthy subjects and evaluated (1) the effect of idelalisib on the pharmacokinetics (PK) of digoxin, a P-gp probe substrate, rosuvastatin, a breast cancer resistance protein, and OATP1B1/OATP1B3 substrate, and midazolam, a CYP3A substrate; and (2) the effect of a strong inducer, rifampin, on idelalisib PK. On treatment, the most common clinical adverse events (AEs) were headache and pyrexia. Grade 3 transaminase increases were observed in 5 of 24 subjects and were reversible. Two subjects had serious AEs after treatment completion (grade 3 pyrexia and/or drug-induced liver injury). Idelalisib coadministration did not affect digoxin and rosuvastatin PK. Coadministration with idelalisib increased plasma exposures of midazolam (138% and 437% for maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUCinf), respectively), consistent with the in vitro finding of CYP3A inhibition by GS-563117. Rifampin caused a substantial decrease in idelalisib (58% and 75%, Cmax and AUCinf , respectively) and GS-563117 exposures, indicating an enhanced contribution of CYP3A to idelalisib metabolism under a strongly induced state.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

口服给药后，中位达峰时间观察到为1.5小时。

Following oral administration, the median Tmax was observed at 1.5 hours.

来源:DrugBank

吸收、分配和排泄

• 消除途径

单次服用150毫克[14C]idelalisib后，放射性物质在粪便中排泄了78%，在尿液中排泄了14%。主要代谢物GS-563117在尿液中的放射性物质占比为49%，在粪便中占比为44%。

Following a single dose of 150 mg of [14C] idelalisib, 78% and 14% of the radioactivity was excreted in feces and urine, respectively. GS-563117, idelalisib's major metabolite, accounted for 49% of the radioactivity in the urine and 44% in the feces.

来源:DrugBank

吸收、分配和排泄

• 分布容积

23升

23 L

来源:DrugBank

吸收、分配和排泄

• 清除

14.9升/小时

14.9 L/hr

来源:DrugBank

吸收、分配和排泄

单次口服150毫克放射性标记的idelalisib后，78%的剂量在粪便中回收，14%在尿液中回收；GS-563117占粪便中回收剂量的44%，占尿液中回收剂量的49%。

Following oral administration of a single 150-mg dose of radiolabeled idelalisib, 78% of the dose was recovered in feces and 14% was recovered in urine; GS-563117 accounted for 44% of the dose recovered in feces and 49% of the dose recovered in urine.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 安全说明：
  SV
• 海关编码：
  29399990
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  室温且干燥

制备方法与用途

艾代拉里斯（idelalisib）是一种首创的高度选择性、口服有效的磷酸肌醇3-激酶delta（PI3K-delta）抑制剂。PI3K-delta信号对于B淋巴细胞的活化、增殖、生存和迁移至关重要，该信号在多种B细胞恶性肿瘤中过度活跃。目前，吉利德正开发idelalisib作为单一制剂，以及与一些已获批的疗法和实验性疗法配伍，用于不同类型血癌的治疗。

艾代拉里斯片是由美国吉利德科学公司研发并于2014年7月在美国上市。Zydelig是一种激酶抑制剂，适用于复发慢性淋巴细胞性白血病（CLL）、复发滤泡B-细胞非霍奇金淋巴瘤（FL）及复发性小淋巴细胞淋巴瘤（SLL）的治疗。

生物活性 idelalisib (CAL-101, GS-1101) 是选择性p110δ抑制剂，在无细胞试验中IC50为2.5 nM；对 p110δ表现出的选择性是对 p110α/β/γ 的40到300倍，对p110δ的选择性是对 C2β、hVPS34、DNA-PK 和 mTOR的400到4000倍。idelalisib 还可诱导自噬。

靶点

Target	Value
p110δ (Cell-free assay)	2.5 nM
p110γ (Cell-free assay)	89 nM

体外研究 CAL-101对p110α、p110β和p110γ的作用效果不大。CAL-101作用于原代嗜碱细胞特定阻断FcϵR1 p110δ调节的CD63表达，EC50为8 nM。与急性髓性白血病（AML）和骨髓增生性肿瘤（MPN）细胞相比，CAL-101 作用于B-cell急性淋巴细胞白血病（B-ALL）和慢性淋巴细胞白血病（CLL）细胞时显示更强的活性。CAL-101 作用于SU-DHL-5, KARPAS-422 和CCRF-SB细胞，降低pAktS473、pAktT308及下游靶点S6，EC50为0.1到1.0 μM。CAL-101 作用于CLL 细胞，诱导选择性细胞毒性，主要通过caspase依赖机制。与正常B细胞相比，CAL-101 作用于CLL 细胞优先产生细胞毒性，并且其对其他造血细胞的毒性低于LY294002。CAL-101 对T 细胞和天然杀伤细胞缺乏直接的细胞毒性潜能。CAL-101 抑制炎症细胞因子的产生，如IL-6、IL-10、TNF-α 和IFN-γ，并激活诱导的细胞因子，如CD40L。CAL-101 也抗CD40L调节的CLL细胞存活。CAL-101 作用于L1236和L591细胞, 引起细胞在G1期积累，在S期下降，说明其可以作为治疗霍杰金淋巴瘤（HL）的一种新策略。

反应信息

• 作为反应物：
  描述：

  艾代拉利司 在 氘 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 80.0 ℃ 、200.0 kPa 条件下， 反应 36.0h， 生成 (S)-2-(1-((9H-purin-6-yl-2,8-d2)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one
  参考文献：
  名称：

  使用氢同位素交换有效地获得氘代和Tri化的Nucleobase药品和寡核苷酸。

  摘要：

  描述了一种有效的氢-同位素交换核碱基衍生物的通用方法。在温和的反应条件下，以钌纳米颗粒为催化剂，并以D 2或T 2为同位素源，该反应具有较宽的底物范围和较高的耐溶剂性。这种新颖的方法有助于在药物发现和开发中使用基本的诊断工具：具有高比活性的tri代药物和适合在LC-MS定量过程中用作内部标准品的氘代寡核苷酸。

  DOI：

  10.1002/anie.201813946
• 作为产物：
  描述：

  (S)-2-(1-((2-chloro-7H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Chloro-idelalisib) 在 palladium 10% on activated carbon 、 氢气 、 sodium acetate 作用下， 以 乙醇 为溶剂， 反应 16.0h， 生成 艾代拉利司
  参考文献：
  名称：

  [EN] PROCESSES FOR PREPARATION OF IDELALISIB AND INTERMEDIATES THEREOF
  [FR] PROCÉDÉS DE PRÉPARATION D'IDÉLALISIB ET DE SES INTERMÉDIAIRES

  摘要：

  公开号：

  WO2016108206A3
• 作为试剂：
  描述：

  2-[(1S)-1-氨基丙基]-5-氟-3-苯基-4(3H)-喹唑啉酮 、 6-溴嘌呤 、 N,N-二异丙基乙胺 在 水 、 crude product 、 甲醇 、 silica gel 、 艾代拉利司 、 hexanes 作用下， 以 叔丁醇 、 乙醇 为溶剂， 反应 24.0h， 生成 艾代拉利司
  参考文献：
  名称：

  Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta

  摘要：

  本发明提供了一类取代喹唑啉酮化合物及其治疗PI3Kδ活性介导的疾病的方法。所披露的化合物可用于治疗骨吸收紊乱等疾病；以及癌症，特别是造血系统肿瘤、淋巴瘤、多发性骨髓瘤和白血病。该化合物还可用于破坏或抑制细胞过程，如白细胞功能或积累、中性粒细胞功能、淋巴细胞增殖和内源性免疫反应。

  公开号：

  US07932260B2

文献信息

• [EN] TANK-BINDING KINASE INHIBITOR COMPOUNDS<br/>[FR] COMPOSÉS INHIBITEURS DE KINASES SE LIANT À TANK
  申请人：GILEAD SCIENCES INC

  公开号：WO2015187684A1

  公开（公告）日：2015-12-10

  Compounds having the following formula (I) and methods of their use and preparation are disclosed:

  揭示了具有以下化学式（I）的化合物及其使用和制备方法。
• Use of Inhibitors of the Activity or Function of PI3K
  申请人：NOVARTIS AG

  公开号：US20150342951A1

  公开（公告）日：2015-12-03

  The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.

  该发明涉及PI3K抑制剂的新用途，其中所述抑制剂对PI3K同工酶δ具有抑制作用，用于治疗患有疟疾、利什曼病、锥虫病、弓形虫病和/或神经囊虫病等疾病或紊乱的受试者的免疫病理学，通过对感染受试者的TLR9的功能抑制。
• TANK-BINDING KINASE INHIBITOR COMPOUNDS
  申请人：Gilead Sciences, Inc.

  公开号：US20160096827A1

  公开（公告）日：2016-04-07

  Compounds having the following formula (I) and methods of their use and preparation are disclosed:

  具有以下化学式（I）的化合物以及它们的使用和制备方法已被披露：
• 一种艾代拉里斯制备方法
  申请人：盐城师范学院

  公开号：CN108409740B

  公开（公告）日：2020-05-08

  本发明提供了公开了一种新的艾代拉里斯制备方法，属于药物合成领域。包括以下步骤：由化合物A在适当溶剂中，在缚酸剂存在下，和B发生亲核取代反应得到中间体C；化合物C在适当的碱作用下水解成中间体D；中间体D与化合物E缩合得到中间体F；中间体F在适当的溶剂中，在六甲基二硅胺(HMDS)/路易斯酸的催化体系下关环反应得到最终产物艾代拉里斯。
• PD-1/PD-L1 INHIBITORS
  申请人：Gilead Sciences, Inc.

  公开号：US20200017471A1

  公开（公告）日：2020-01-16

  Compounds and methods of using said compounds singly or in combination with additional agents and compositions of said compounds for the treatment of cancer are disclosed.

  披露了化合物以及单独使用或与附加剂组合使用这些化合物的方法，以及用于治疗癌症的这些化合物的组合物。