每周分子 | Molecule of the Week
每周分子 | Molecule of the Week
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每周分子： ( R )-劳拉替尼
Molecule of the Week: ( R )-Lorlatinib
( R )-劳拉替尼 1 是一种用于治疗间变性淋巴瘤激酶 (ALK) 阳性非小细胞肺癌的口服药物。而ALK阳性非小细胞肺癌对于早前的癌症治疗药物克唑替尼 2 已有耐药性。辉瑞公司 (美国纽约市) 在2013年的一项全球专利申请中首次公开了这一药物 。
2014年，来自辉瑞全球研发中心 (美国圣迭戈) 的Ted W. Johnson、Paul F. Richardson及其同事公开了一项研究发现，时称PF-06463922。通过药物结构设计、亲脂性效率考虑和物理性质的优化，他们合成了具备有效控制癌症特性的大环ALK抑制剂。这些抑制剂对于野生型ALK和临床报道的ALK结构域突变具有很强的药效。PF-06463922成为了最佳候选药物 。
美国食品药品监督管理局于2014年授予劳拉替尼孤儿药资格，并于2018年全面批准将其用于ALK阳性转移性非小细胞肺癌的二线或三线治疗。欧洲药品管理局于2019年效仿此举。次年，澳大利亚医疗信息提供机构NPS MedicineWise发布了一份劳拉替尼说明书 3 。
1 SciFinder命名: 2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, 7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-, (10R)-.
2 CAS Reg. No. 877399-52-5
3. https://www.nps.org.au/australian-prescriber/articles/lorlatinib-for-non-small-cell-lung-cancer
( R )-劳拉替尼信息速览
CAS 登记号 |
1454846-35-5 |
分子式 |
C 21 H 19 FN 6 O 2 |
摩尔质量 |
406.41 g/mol |
外观 |
白色结晶或粉末 |
熔点 |
184–187 °C |
水溶性 |
不溶 |
( R )-劳拉替尼危害信息
GHS分类：生殖细胞致突变性，分类2 |
|
H341-疑似导致遗传性缺陷 |
|
GHS分类：特异性靶器官毒性，肝脏和胰脏，反复接触，分类2 |
|
H373-长期或反复接触可能对肝脏或胰脏造成伤害 |
|
【 关于每周分子 】
自2001年以来，“每周分子”已成为广受欢迎的栏目。多数分子由读者推荐。每个结构都经由科学家审查，并以3-D和平面图像的形式显示，同时附有该分子简介。可以通过美国化学文摘社 (CAS) 提供的CAS SciFinder n 中的CAS REGISTRY获取“每周分子”的更多信息。CAS REGISTRY中的每条物质信息都展示了物质的CAS登记号、索引名、通用名、商品名、书目信息等其他更多信息。 发送邮件至motw@acs.org推荐您感兴趣的分子吧 。
( R )-Lorlatinib 1 is an oral medication for treating anaplastic lymphoma kinase (ALK)–positive non–small-cell lung carcinomas resistant to crizotinib 2 , an earlier drug used to combat the cancer. It was first disclosed by Pfizer (New York City) in a 2013 world patent application.
In 2014, Ted W. Johnson, Paul F. Richardson, and colleagues at Pfizer Worldwide Research and Development (San Diego) described the discovery of what was then called PF-06463922. They used structure-based drug design, lipophilic efficiency considerations, and physical-property–based optimization procedures to synthesize potent macrocyclic ALK inhibitors with the desired characteristics for effective carcinoma control. The inhibitors were potent against wild-type ALK and clinically reported ALK domain mutations. PF-06463922 emerged as the optimum drug candidate.
The US Food and Drug admin126459646istration granted orphan status to lorlatinib in 2014 and full approval in 2018 for second- or third-line treatment of ALK-positive metastatic non-small-cell-lung-cancer. The European Medicines Agency followed suit in 2019. The following year, NPS MedicineWise, an Australian medical information provider, issued a fact sheet for lorlatinib 3 .
1 SciFinder: 2H-4,8-methenopyrazolo[4,3-h][2,5,11]benzoxadiazacyclotetradecine-3-carbonitrile, 7-amino-12-fluoro-10,15,16,17-tetrahydro-2,10,16-trimethyl-15-oxo-, (10R)-.
2 CAS Reg. No. 877399-52-5
3. https://www.nps.org.au/australian-prescriber/articles/lorlatinib-for-non-small-cell-lung-cancer
( R )-Lorlatinib fast facts
CAS Reg. No. |
1454846-35-5 |
|
Empirical formula |
C 21 H 19 FN 6 O 2 |
Molar mass |
406.41 g/mol |
Appearance |
White crystals or powder |
Melting point |
184–187 °C |
Water solubility |
Insoluble |
( R )-Lorlatinib hazard information
Germ cell mutagenicity, category 2 |
|
H341-Suspected of causing genetic defects |
|
Specific target organ toxicity, liver and pancreas,repeated exposure, category 2 |
|
H373-May cause damage to the liver and pancreas throughprolonged or repeated exposure |
|
About Molecule of the Week
MOTW has been a popular feature on ACS website since 2001. Many molecules are suggested by our website visitors. Every structure is reviewed by a scientist and displayed in 3-D and flat images with a brief description. Each week’s molecule also links to a sample record from the CAS REGISTRY, which is searched using CAS SciFinder n . Each record displays the registry number, index name and synonyms, bibliographic information, and more. Send us a molecule suggestion at motw@acs.org .
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