临床候选3-(2-{3-[(2,4-二氨基-6-乙基嘧啶-5-基)氧]丙氧基}苯基)丙酸(P218)及其羟基化代谢物的实用合成方法的建立

IF 2.2 4区化学 Q2 CHEMISTRY, ORGANIC

Synthesis-Stuttgart Pub Date : 2023-10-30 DOI:10.1055/s-0042-1751502

Nitipol Srimongkolpithak, Onanong Vorasin, Tanawat Phumjan, Siriporn Saepua, Daniel Iwaniuk, Sumalee Kamchonwongpaisan, Yongyuth Yuthavong, Chawanee Thongpanchang

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引用次数: 0

摘要

摘要3-(2-{3-[(2,4-二氨基-6-乙基嘧啶-5-基)氧]丙氧基}苯基)丙酸(P218)在临床前和人体研究中显示出良好的效力和安全性。然而，先前的P218合成方法收率低，需要危险的试剂和具有挑战性的程序。在这项研究中，我们成功地开发了P218的十克级合成路线，具有实用和可扩展的大规模生产方法。此外，这也是首次报道通过修改我们的发现途径，合成P218- oh (P218的羟基化代谢物)的新方法。我们的P218和P218- oh的合成方法在药物开发过程中取得了重大进展，包括制造过程和药物代谢研究。

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Development of a Practical Synthetic Method for Clinical Candidate 3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy} phenyl)propanoic acid (P218) and Its Hydroxylated Metabolites

Abstract 3-(2-{3-[(2,4-Diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid, known as P218, has demonstrated great potency and safety in preclinical and human studies. However, the previous synthetic methods for P218 gave low yields and required hazardous reagents and challenging procedures. In this study, we have successfully developed a decagram-scale synthetic route for P218 with practical and scalable methods for large-scale production. Furthermore, this is also a first report of a novel synthetic approach for P218-OH, a hydroxylated metabolite of P218, by modification of our discovery route. Our synthetic procedures for P218 and P218-OH are a significant advancement in drug development processes, including manufacturing processes and drug metabolism studies.

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来源期刊

Synthesis-Stuttgart 化学-有机化学

CiteScore

4.50

自引率

7.70%

发文量

435

审稿时长

1 months

期刊介绍： SYNTHESIS is an international full-paper journal devoted to the advancement of the science of chemical synthesis. It covers all fields of organic chemistry involving synthesis, including catalysis, organometallic, medicinal, biological, and photochemistry, but also related disciplines. SYNTHESIS provides dependable research results with detailed and reliable experimental procedures and full characterization of all important new products as well as scientific primary data.