2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲磺酰基)苯甲酰胺 | 879085-55-9

• 物质功能分类: 生物化工 - 抑制剂 - 干细胞及Wnt信号通路(Stem Cells & Wnt)
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲磺酰基)苯甲酰胺
• 中文别名: 2-氯-n-[4-氯-3-(2-吡啶)苯基]-4-(甲基磺酰基)苯甲酰胺；维莫德吉
• 英文名称: vismodegib
• 英文别名: GDC-0449；2-chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide；erivedge；2-chloro-N-[4-chloro-3-(pyridin-2-yl)phenyl]-4-methanesulfonylbenzamide；2-chloro-N-(4-chloro-3-(2-pyridyl)phenyl)-4-(methylsulfonyl)benzamide
• CAS: 879085-55-9
• 化学式: C₁₉H₁₄Cl₂N₂O₃S
• 分子量: 421.304
• InChiKey: BPQMGSKTAYIVFO-UHFFFAOYSA-N

物化性质

• 熔点：
  179-181°C
• 沸点：
  561.6±50.0 °C(Predicted)
• 密度：
  1.440
• 溶解度：
  可溶于DMSO（高达200mg/ml）或乙醇（加热时高达10mg/ml）
• 颜色/状态：
  Crystalline
• 蒸汽压力：
  7.6X10-14 mm Hg at 25 °C (est)
• 解离常数：
  pKa = 3.8 (pyridinium cation)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  84.5
• 氢给体数：
  1
• 氢受体数：
  4

ADMET

代谢

主要代谢酶是CYP2C9和CYP3A4，然而，超过98%的维莫德吉总剂量并未发生代谢。维莫德吉在人体的代谢途径包括氧化、葡萄糖醛酸化和吡啶环断裂。在粪便中回收到的两个最丰富的氧化代谢物是通过重组CYP2C9和CYP3A4/5在体外产生的。

The main metabolic enzymes are CYP2C9 and CYP3A4, however more than 98% of total systemic vismodegib is not metabolized. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5.

来源:DrugBank

代谢

大于98%的总循环药物相关成分是母药。维莫德吉（vismodegib）在人体内的代谢途径包括氧化、葡萄糖醛酸化和吡啶环裂解。在粪便中回收到的两个最丰富的氧化代谢物是通过重组CYP2C9和CYP3A4/5在体外产生的。

Greater than 98% of the total circulating drug-related components are the parent drug. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation, and pyridine ring cleavage. The two most abundant oxidative metabolites recovered in feces are produced in vitro by recombinant CYP2C9 and CYP3A4/5.

来源:Hazardous Substances Data Bank (HSDB)

代谢

2-氯-N-(4-氯-3-(吡啶-2-基)-苯基)-4-(甲磺酰基)苯甲酰胺（GDC-0449，维莫德吉）是一种强效且选择性的首类小分子Hedgehog信号通路的抑制剂，目前正处于临床开发阶段。在本研究中，我们调查了在大鼠和狗单次口服给药(14)C-GDC-0449后，GDC-0449的代谢命运和处置。... GDC-0449在大鼠和狗体内经历了广泛的代谢，主要的代谢途径是4-氯-3-(吡啶-2-基)-苯基部分的氧化，随后是二期葡萄糖苷酸化或硫酸化。还发现了三种其他代谢物，它们来源于不常见的吡啶环开环，主要分布在粪便中，在大鼠和狗体内总共占给药剂量的1.7%到17.7%。...

2-Chloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(methylsulfonyl)-benzamide (GDC-0449, vismodegib) is a potent and selective first-in-class small-molecule inhibitor of the Hedgehog signaling pathway and is currently in clinical development. In this study, we investigated the metabolic fate and disposition of GDC-0449 in rats and dogs after a single oral administration of (14)C-GDC-0449. ... GDC-0449 underwent extensive metabolism in rats and dogs with the major metabolic pathways being oxidation of the 4-chloro-3-(pyridin-2-yl)-phenyl moiety followed by phase II glucuronidation or sulfation. Three other metabolites resulting from an uncommon pyridine ring opening were found, mainly in feces, representing 1.7 to 17.7% of the dose in total in rats and dogs. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

体外（大鼠、狗和人类肝脏微粒体）和体内（狗和大鼠尿液）探索性代谢物鉴定提出的代谢物包括三个主要氧化代谢物（M1-M3）和三个连续的葡萄糖苷酸（M4-M6）。在微粒体中鉴定的氧化代谢物M1和M3主要是由P4503A4/5（M1）和P4502C9（M3）形成的。GDC-0449不是P4501A2、P4502B6、P4502D6和P4503A4/5的强抑制剂，IC50估计值大于20微摩尔。对P4502C8、P4502C9和P4502C19的K(i)估计分别为6.0、5.4和24微摩尔。Simcyp的评估表明，GDC-0449抑制P4502C8和P4502C9的潜力较低。此外，GDC-0449（15微摩尔）在MDR1-MDCK细胞中不是P-糖蛋白/ABCB1的强抑制剂。

... Proposed metabolites from exploratory metabolite identification in vitro (rat, dog and human liver microsomes) and in vivo (dog and rat urine) include three primary oxidative metabolites (M1-M3) and three sequential glucuronides (M4-M6). Oxidative metabolites identified in microsomes M1 and M3 were formed primarily by P4503A4/5 (M1) and P4502C9 (M3). GDC-0449 was not a potent inhibitor of P4501A2, P4502B6, P4502D6, and P4503A4/5 with IC50 estimates greater than 20 uM. K(i)'s estimated for P4502C8, P4502C9 and P4502C19 and were 6.0, 5.4 and 24 uM, respectively. An evaluation with Simcyp suggests that GDC-0449 has a low potential of inhibiting P4502C8 and P4502C9. Furthermore, GDC-0449 (15 uM) was not a potent P-glycoprotein/ABCB1 inhibitor in MDR1-MDCK cells.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

大多数维莫德吉临床试验包括的患者数量较少，肝功能测试异常的发生率通常没有报告。维莫德吉的产品标签中没有提到血清酶升高或肝毒性的情况。然而，对所有已发表的维莫德吉研究进行的后续审查提到，在接受治疗的363名患者中，有1.4%出现了肝酶升高。自从其获得批准并更广泛使用以来，出现了与维莫德吉相关的临床上明显的肝损伤报告。在一项报告中，一名老年男性在开始服用维莫德吉41天后出现疲劳、恶心和黄疸，血清酶升高呈现胆汁淤积模式，停药后迅速改善（案例1）。此外，对过去7年向FDA自发报告的不良事件审查发现，在维莫德吉治疗期间有94例肝毒性报告，其中包括20例被认为是严重的，4例导致肝衰竭。因此，维莫德吉引起的临床上明显的肝损伤虽然发生，但相对较为罕见。

Most clinical trials of vismodegib included few patients and rates of liver tests abnormalities were usually not reported. The product label for vismodegib includes no mention serum enzyme elevations or hepatotoxicity. However, a subsequent review of all published studies of vismodegib mentions that liver enzyme elevations occurred in 1.4% of a total of 363 patients treated. Since its approval and more general use, reports of clinically apparent liver injury linked to vismodegib have appeared. In one report, an elderly man presented with fatigue, nausea and jaundice 41 days after starting vismodegib with a cholestatic pattern of serum enzyme elevations and rapid improvement on stopping (Case 1). In addition, review of 7 years of spontaneous adverse event reporting to the FDA revealed 94 reports of hepatotoxicity during vismodegib therapy, including 20 that were considered serious and 4 that resulted in hepatic failure. Thus, clinically apparent liver injury from vismodegib occurs, but is somewhat rare.

来源:LiverTox

毒理性

• 相互作用

改变上消化道pH的药物（例如质子泵抑制剂、H2受体拮抗剂和抗酸药）可能会改变维莫德吉的溶解性并降低其生物利用度。然而，尚未进行正式的临床研究来评估胃pH改变剂对维莫德吉系统暴露的影响。当与这些药物联合使用时，增加艾瑞威格的剂量不太可能补偿暴露的损失。当艾瑞威格与质子泵抑制剂、H2受体拮抗剂或抗酸药联合使用时，维莫德吉的系统暴露可能会降低，对艾瑞威格疗效的影响未知。

Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of Erivedge when coadministered with such agents is not likely to compensate for the loss of exposure. When Erivedge is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of Erivedge is unknown.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

体外研究显示，维莫德吉是外排转运蛋白P-糖蛋白（P-gp）的底物。当“Erivedge”与抑制P-gp的药物（例如克拉霉素、红霉素、阿奇霉素）联合使用时，维莫德吉的系统暴露量以及“Erivedge”的不良事件发生率可能会增加。

In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When Erivedge is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of Erivedge may be increased.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

维莫德吉的消除涉及多种途径。维莫德吉主要以原药形式排泄。多种CYP酶产生了几个次要代谢物。尽管维莫德吉在体外是CYP2C9和CYP3A4的底物，但预计CYP抑制不会改变维莫德吉的系统暴露，因为在临床试验中，同时接受CYP3A4诱导剂（即，卡马西平、莫达非尼、苯巴比妥）治疗的患者和同时接受CYP3A4抑制剂（即，红霉素、氟康唑）治疗的患者中观察到了类似的稳态血浆维莫德吉浓度。

Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole).

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

Vismodegib是一种首创的口服Hedgehog信号通路抑制剂，是治疗晚期基底细胞癌的有效药物。根据体外数据，需要对细胞色素P450（CYP）2C8进行临床药物-药物相互作用（DDI）评估；Vismodegib的致畸潜能使得进行与口服避孕药（OC）的DDI研究成为必要。这项单臂、开放标签的研究包括了两队列患有局部晚期或转移性实体恶性肿瘤的患者[队列1：罗格列酮4mg（选择性CYP2C8探针）；队列2：OC（炔诺酮1mg/乙炔雌二醇35ug；CYP3A4底物）]。在第1天，患者接受罗格列酮或OC。在第2-7天，患者接受Vismodegib 150 mg/天。在第8天，患者接受Vismodegib加罗格列酮或OC。通过24小时内的药代动力学采样（第1天和第8天）评估了Vismodegib对罗格列酮和OC药代动力学参数（主要目标）的影响。 结果：Vismodegib稳态血浆浓度（第8天，N=51）的平均值±SD为20.6±9.72 uM（范围7.93-62.4 uM）。罗格列酮AUC(0-inf)和C(max)与同时使用Vismodegib相似[=8%的几何平均比值（GMRs）变化；N=24]。与OC同时使用Vismodegib并不影响乙炔雌二醇AUC(0-inf)和C(max)[=5%的GMRs变化；N=27]；炔诺酮C(max)和AUC(0-inf)的GMRs更高（分别为12%和23%）。结论：这项癌症患者的DDI研究表明，当同时使用Vismodegib时，罗格列酮（CYP2C8底物）或OC（乙炔雌二醇/炔诺酮）的系统性暴露没有改变。总体来看，当Vismodegib与其他药物联合使用时，似乎DDI的潜力较低。

Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs). This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 ug; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8). RESULTS: The mean + or - SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 + or - 9.72 uM (range 7.93-62.4 uM). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [=8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (=5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib. CONCLUSIONS: This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

• 吸收

单次剂量的绝对生物利用度为31.8%。吸收具有饱和性，且不受食物影响。

The absolute bioavailability of a single dose is 31.8%. Absorption is saturable and is not affected by food.

来源:DrugBank

吸收、分配和排泄

• 消除途径

Vismodegib大部分以原型药物形式排泄，主要排泄途径是通过粪便（82%），尿液占4.4%。

Vismodegib is mostly excreted unchanged, and the main route of elimination is by the feces (82%) and the urine accounts for 4.4%.

来源:DrugBank

吸收、分配和排泄

• 分布容积

维莫德吉的分布体积为16.4至26.6升。

Vismodegib has a volume of distribution of 16.4 to 26.6 L.

来源:DrugBank

吸收、分配和排泄

vismodegib的分布容积范围为16.4至26.6升。患者体内的vismodegib血浆蛋白结合率大于99%。Vismodegib与人类血清白蛋白和α-1-酸性糖蛋白（AAG）结合，且与AAG的结合是可饱和的。

The volume of distribution of vismodegib ranges from 16.4 to 26.6 L. Vismodegib plasma protein binding in patients is greater than 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) and binding to AAG is saturable.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

vismodegib单次剂量的绝对生物利用度为31.8%。吸收是可饱和的，这通过在单次剂量270毫克或540毫克vismodegib后暴露量没有剂量比例增加来证明。Erivedge胶囊可以在不考虑进餐的情况下服用，因为在稳态时vismodegib的系统暴露不受食物影响。

The single dose absolute bioavailability of vismodegib is 31.8%. Absorption is saturable as evidenced by the lack of dose proportional increase in exposure after a single dose of 270 mg or 540 mg vismodegib. Erivedge capsule may be taken without regard to meals because the systemic exposure of vismodegib at steady state is not affected by food.

来源:Hazardous Substances Data Bank (HSDB)

安全信息

• 海关编码：
  2933399090
• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335,H351,H361
• 储存条件：
  室温且干燥

制备方法与用途

维莫德吉概述

维莫德吉（ViSMOdegib），商品名为：Erivedge；是由Genentech有限公司申请开发的并于2012年1月30日被美国食品药品监督管理局（FDA）批准上市，用于治疗晚期皮肤基底细胞癌（BCC）。自2012年10月以来，Erivedge已获欧盟、瑞士、澳大利亚、以色列、韩国和墨西哥等国家和地区批准。

用途

维莫德吉主要用于手术后复发或不适于手术或放疗治疗的成人局部进行性或转移性基底细胞癌（BCC）。基底细胞癌是最常见的皮肤癌之一，源于皮肤表层，患者一般不会感到疼痛。经常暴露在阳光下或紫外线照射的人群患此病的概率较大。维莫德吉的研发上市对BCC患者带来了福音，其临床作用重要且目标市场巨大，未来具有成长为“巨型炸弹”级（＞10亿美元）药物的潜力。

作用机制

维莫德吉是一种选择性Hedgehog信号传导刺猬通路抑制剂，其新型作用机制在生命早期活跃并对人的生长和发育起着重要作用。然而，在成人中不活跃。基底细胞癌患者绝大多数（＞90%）存在Hedgehog信号传导通路过度活跃现象，被认为是基底细胞癌的基础分子驱动者。维莫德吉作为竞争性的环杷明（Cyclopamine）拮抗剂，作用于Hedgehog信号通路中的跨膜G蛋白偶联受体蛋白（SMOothened），通过抑制SMO受体使转录因子GLT-1和GLT-2保持非活化状态，从而阻断Hedgehog信号通路上相关的肿瘤调节基因的表达。

合成路线

临床实验过程

维莫德吉是美国FDA批准的第一个用于治疗进行性基底细胞癌的药物。主要依据一项代号为SHH4476g的研究，该研究是一项国际性的、多中心的、单组的两队列开放性Ⅱ期临床试验数据作出的批准决定。该试验共包括96例局部进行性（71例）和转移性（33例）基底细胞癌患者，均接受维莫德吉150 mg/d治疗直至疾病进展或出现不能接受的毒性为止，主要终点为由独立专家小组评判的客观应答率。研究结果显示，维莫德吉治疗的局部进行性和转移性基底细胞癌患者的客观应答率分别为43%和33%，中值应答时间是7.6个月。

副反应

维莫德吉最常见的副反应包括肌肉痉挛、脱发、味觉改变或丧失、体重下降、疲乏、恶心、腹泻、食欲降低、便秘、呕吐和关节痛。维莫德吉有致畸性，育龄患者接受该药治疗期间必须采取避孕措施。

用药

维莫德吉以一日1次口服方案用药。

参考文献

1. 杨明伦. (2013). 2012年美国FDA批准上市的抗肿瘤新药. 药学服务与研究, 4期, 304-306.
2. 谭初兵, 时丽丽, 王士伟等. (2013). 2012年美国FDA批准新药介绍和分析. 现代药物与临床, 28(3), 415-420.
3. 佚名. (2015). 罗氏新药维莫德吉用于治疗转移性基底细胞癌(BCC). 临床合理用药杂志, 17期, 158-158.
4. 罗氏ViSMOdegib用于治疗转移性基底细胞癌

用途

维莫德吉还用作医药中间体和有机合成中间体。

反应信息

• 作为反应物：
  描述：

  2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲磺酰基)苯甲酰胺 在 4-二甲氨基吡啶 、 silver(II) fluoride 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 14.0h， 生成 methyl N-[4-chloro-3-(6-fluoropyridin-2-yl)phenyl]-N-(2-chloro-4-methylsulfonylbenzoyl)carbamate
  参考文献：
  名称：

  通过 C-H 氟化和亲核芳香取代合成和后期功能化复杂分子

  摘要：

  我们报告了多取代吡啶和二嗪在氮的 α 位的后期功能化。通过这个过程，安装了一系列通过氮、氧、硫或碳与环结合的官能团和取代基。这种官能化是通过氟化和安装的氟化物的亲核芳族取代的组合来完成的。由于 2-氟杂芳烃的亲核芳香取代 (SNAr) 显示出温和的反应条件，因此可以安装多种功能。替代率与竞争过程率的评估提供了规划此功能化序列的框架。这个过程通过一系列具有药用价值的化合物的修饰来说明，

  DOI：

  10.1021/ja5049303
• 作为产物：
  描述：

  2-(2-chlorophenyl)pyridine 在 二茂铁 、 2,6-二叔丁基吡啶 、 3,5-二氟-2-吡啶羧酸 、 六氟异丙醇 、 potassium carbonate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 72.08h， 生成 2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲磺酰基)苯甲酰胺
  参考文献：
  名称：

  通过非共价相互作用推进元选择性 C–H 胺化

  摘要：

  简单芳烃的区域选择性 C-H 胺化是非常理想的，但由于缺乏电子和空间偏好，访问普遍存在的芳烃的元位点已被证明具有挑战性。这项研究证明了成功地利用药物化合物中发现的各种独特的含氮官能团来指导芳烃的间-C-H胺化，克服了长期以来对冗余导向基团的要求。通过发现前所未有的有机引发剂和非共价相互作用的战略利用，在精确区域化学控制的官能团调节方面取得了显着进展。该方案已成功应用于药物分子的简洁合成和后期衍生化，否则这是很难实现的。

  DOI：

  10.1021/jacs.3c09904

文献信息

• [EN] COMPOUNDS AND COMPOSITIONS FOR INHIBITING THE ACTIVITY OF SHP2<br/>[FR] COMPOSÉS ET COMPOSITIONS POUR INHIBER L'ACTIVITÉ DE SHP2
  申请人：NOVARTIS AG

  公开号：WO2016203404A1

  公开（公告）日：2016-12-22

  The present invention relates to compounds of formula I. The compounds are inhibitors of the Src Homolgy-2 phosphatase (SHP2) and thus useful in the treatment of Noonan Syndrome, Leopard Syndrome and cancer.

  本发明涉及式I的化合物。这些化合物是Src同源-2磷酸酶（SHP2）的抑制剂，因此在努南综合征、豹纹综合征和癌症的治疗中有用。
• [EN] NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS<br/>[FR] NOUVEAUX COMPOSÉS 2-PIPERIDIN-1-YL-ACETAMIDE UTILISABLES EN TANT QU'INHIBITEURS DE TANKYRASE
  申请人：NOVARTIS AG

  公开号：WO2013012723A1

  公开（公告）日：2013-01-24

  The present invention provides for compounds of formula (I), wherein R1-R5 and L are defined herein. The present invention also provides for pharmaceutical compositions and combinations comprising a compound of formula (I) as well as for the use of such compounds as tankyrase inhibitors and in the treatment of Wnt signaling and tankyrase 1 and 2 signaling related disorders which include, but are not limited to, cancer.

  本发明提供了式(I)的化合物，其中R1-R5和L在此处定义。本发明还提供了包含式(I)化合物的药物组合物和组合物，以及将这些化合物用作坦基酶抑制剂以及用于治疗Wnt信号和坦基酶1和2信号相关疾病的用途，包括但不限于癌症。
• Uniting Amide Synthesis and Activation by P^III/P^V–Catalyzed Serial Condensation: Three-Component Assembly of 2-Amidopyridines
  作者：Jeffrey M. Lipshultz、Alexander T. Radosevich

  DOI：10.1021/jacs.1c07608

  日期：2021.9.15

  An organophosphorus (PIII/PV redox) catalyzed method for the three-component condensation of amines, carboxylic acids, and pyridine N-oxides to generate 2-amidopyridines via serial dehydration is reported. Whereas amide synthesis and functionalization usually occur under divergent reaction conditions, here a phosphetane catalyst (together with a mild bromenium oxidant and terminal hydrosilane reductant)

  报道了一种有机磷（P III /P V氧化还原）催化胺、羧酸和吡啶N-氧化物三组分缩合通过连续脱水生成 2-氨基吡啶的方法。虽然酰胺合成和官能化通常发生在不同的反应条件下，但此处显示膦烷催化剂（与温和的溴氧化剂和末端氢硅烷还原剂一起）在自动串联催化级联中以化学选择性驱动这两个步骤。在单一有机催化活性中间体的作用下制备和官能化酰胺的能力为高效和模块化制备药物靶标提供了新的可能性。
• A General Strategy for Site-Selective Incorporation of Deuterium and Tritium into Pyridines, Diazines, and Pharmaceuticals
  作者：J. Luke Koniarczyk、David Hesk、Alix Overgard、Ian W. Davies、Andrew McNally

  DOI：10.1021/jacs.7b11710

  日期：2018.2.14

  molecules are valuable for medicinal chemistry. The prevalence of pyridines and diazines in pharmaceuticals means that new ways to label these heterocycles will present opportunities in drug design and facilitate absorption, distribution, metabolism, and excretion (ADME) studies. A broadly applicable protocol is presented wherein pyridines, diazines, and pharmaceuticals are converted into heterocyclic phosphonium

  将氘和氚原子结合到有机分子中的方法对于药物化学很有价值。药物中吡啶和二嗪的流行意味着标记这些杂环的新方法将为药物设计提供机会，并促进吸收、分布、代谢和排泄 (ADME) 研究。提出了一个广泛适用的协议，其中吡啶、二嗪和药物被转化为杂环鏻盐，然后进行同位素标记。同位素以高产率掺入，并且通常具有独特的区域选择性。
• Visible‐Light‐Induced <i>ortho</i> ‐Selective Migration on Pyridyl Ring: Trifluoromethylative Pyridylation of Unactivated Alkenes
  作者：Jinwon Jeon、Yu‐Tao He、Sanghoon Shin、Sungwoo Hong

  DOI：10.1002/anie.201912746

  日期：2020.1.2

  alkenes. The overall process is initiated by the selective addition of a CF3 radical to the alkene to provide a nucleophilic alkyl radical intermediate, which enables an intramolecular endo addition exclusively to the ortho-position of the pyridinium salt. Both secondary and tertiary alkyl radicals are well-suited for addition to the C2-position of pyridinium salts to ultimately provide synthetically

  对于未活化的烯烃的位点选择性三氟甲基化吡啶基化，已经实现了在吡啶基环上的光催化邻位选择性迁移。整个过程是通过将CF3自由基选择性地添加到烯烃中以提供亲核烷基自由基中间体而启动的，该中间体能够将分子内的内含物专门添加到吡啶鎓盐的邻位。仲烷基和叔烷基都非常适合于添加吡啶鎓盐的C 2-位，以最终提供具有合成价值的C 2-氟烷基官能化的吡啶。此外，该方法已成功应用于以P为中心的自由基的反应。复杂生物活性分子的后期功能化进一步证明了这种转化的效用。