Goulet M T, McAlpine S R, Staruch M J, Koprak S, Dumont F J, Cryan J G, Wiederrecht G J, Rosa R, Wilusz M B, Peterson L B, Wyvratt M J, Parsons W H
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA.
Bioorg Med Chem Lett. 1998 Aug 18;8(16):2253-8. doi: 10.1016/s0960-894x(98)00397-7.
A series of C32-O-aralkyl ether derivatives of the FK-506 related macrolide ascomycin have been prepared based on an earlier reported C32-O-cinnamyl ether design. In the present study, the nature of the aryl tethering group was varied in an attempt to improve oral activity. An imidazol-2-yl-methyl tether was found to be superior among those investigated and has resulted in an ascomycin analog, L-733,725, with in vivo immunosuppressive activity comparable to FK-506 but with an improved therapeutic index.
基于先前报道的C32 - O - 肉桂基醚设计，已制备了一系列与FK - 506相关的大环内酯类子囊霉素的C32 - O - 芳烷基醚衍生物。在本研究中，改变芳基连接基团的性质以试图提高口服活性。发现在所研究的基团中，咪唑 - 2 - 基 - 甲基连接基团表现优异，并且由此得到了一种子囊霉素类似物L - 733,725，其体内免疫抑制活性与FK - 506相当，但治疗指数有所提高。
