Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.
Bioorg Med Chem Lett. 2020 Sep 1;30(17):127357. doi: 10.1016/j.bmcl.2020.127357. Epub 2020 Jun 19.
Our previously reported efforts to produce an orally active β-1,3-glucan synthesis inhibitor through the semi-synthetic modification of enfumafungin focused on replacing the C2 acetoxy moiety with an aminotetrazole and the C3 glycoside with a N,N-dimethylaminoether moiety. This work details further optimization of the C2 heterocyclic substituent, which identified 3-carboxamide-1,2,4-triazole as a replacement for the aminotetrazole with comparable antifungal activity. Alkylation of either the carboxamidetriazole at C2 or the aminoether at C3 failed to significantly improve oral efficacy. However, replacement of the isopropyl alpha amino substituent with a t-butyl, improved oral exposure while maintaining antifungal activity. These two structural modifications produced MK-5204, which demonstrated broad spectrum activity against Candida species and robust oral efficacy in a murine model of disseminated Candidiasis without the N-dealkylation liability observed for the previous lead.
我们之前的研究通过对恩芬那滨的半合成修饰来生产一种具有口服活性的β-1,3-葡聚糖合成抑制剂，重点是用氨甲四唑取代 C2 乙酰氧基和用 N,N-二甲氨基醚取代 C3 糖苷。这项工作详细介绍了对 C2 杂环取代基的进一步优化，确定 3-羧酰胺-1,2,4-三唑是可替代氨甲四唑的具有相当抗真菌活性的化合物。C2 位的羧酰胺三唑或 C3 位的氨基醚的烷基化都未能显著提高口服疗效。然而，用叔丁基取代异丙基α-氨基取代基，在保持抗真菌活性的同时，提高了口服暴露量。这两种结构修饰产生了 MK-5204，它对念珠菌属具有广谱活性，并在播散性念珠菌病的小鼠模型中具有良好的口服疗效，而没有观察到之前先导化合物的 N-脱烷基化副反应。
