Scynexis, Inc., PO Box 12878, Research Triangle Park, NC 27709-2878, USA.
Bioorg Med Chem Lett. 2012 Nov 15;22(22):6811-6. doi: 10.1016/j.bmcl.2012.05.031. Epub 2012 May 17.
Orally bioavailable inhibitors of β-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein.
作为新的、广谱抗真菌疗法，口服生物利用的β-(1,3)-D-葡聚糖合成酶抑制剂已被广泛研究，适用于免疫功能低下患者的治疗。为此，我们基于三萜糖苷天然产物恩夫霉素的半合成衍生化，建立了一个合作药物化学项目，旨在优化体内抗真菌活性和口服吸收特性。在这些研究中，我们假设通过将靠近 C3-氨基醚侧链碱性氮的烷基基团连接到一个氮杂环系统中，可以改善半合成恩夫霉素类似物 3 的药代动力学特性，从而避免氧化 N-去甲基化。本文介绍了这一研究工作的结果。
