Dumont F J, Koprak S, Staruch M J, Talento A, Koo G, DaSilva C, Sinclair P J, Wong F, Woods J, Barker J, Pivnichny J, Singer I, Sigal N H, Williamson A R, Parsons W H, Wyvratt M
Department of Immunology Research, Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Transplantation. 1998 Jan 15;65(1):18-26. doi: 10.1097/00007890-199801150-00005.
Tacrolimus (FK506) has potent immunosuppressive properties reflecting its ability to block the transcription of lymphokine genes in activated T cells through formation of a complex with FK506 binding protein-12, which inhibits the phosphatase activity of calcineurin. The clinical usefulness of tacrolimus is limited, however, by severe adverse effects, including neurotoxicity and nephrotoxicity. Although this toxicity, like immunosuppression, appears mechanistically related to the calcineurin inhibitory action of the drug, a large chemistry effort has been devoted to search for tacrolimus analogs with reduced toxicity but preserved immunosuppressive activity that might have enhanced therapeutic utility.
Here, we report on the identification of such an analog, which was synthetically derived from ascomycin (ASC), the C21 ethyl analog of tacrolimus, by introducing an indole group at the C32 position. The profile of biological activity of indolyl-ASC was characterized in rodent models of immunosuppression and toxicity.
Indolyl-ASC was found to exhibit an immunosuppressive potency equivalent to that of tacrolimus in T-cell activation in vitro and in murine transplant models, even though indolyl-ASC bound about 10 times less to intracellular FK506 binding protein-12 than tacrolimus or ASC. Further evaluation of indolyl-ASC revealed that it is threefold less potent than tacrolimus in inducing hypothermia, a response that may reflect neurotoxicity, and in causing gastrointestinal transit alterations in mice. Moreover, indolyl-ASC was at least twofold less nephrotoxic than tacrolimus upon 3-week oral treatment in rats.
Altogether, these data indicate a modest but definite improvement in the therapeutic index for indolyl-ASC compared with tacrolimus in rodent models.
他克莫司（FK506）具有强大的免疫抑制特性，这反映出它能够通过与FK506结合蛋白-12形成复合物来阻断活化T细胞中淋巴因子基因的转录，从而抑制钙调神经磷酸酶的磷酸酶活性。然而，他克莫司的临床应用受到严重不良反应的限制，包括神经毒性和肾毒性。尽管这种毒性与免疫抑制一样，在机制上似乎与该药物的钙调神经磷酸酶抑制作用有关，但人们已经投入了大量的化学研究工作来寻找毒性降低但保留免疫抑制活性的他克莫司类似物，这些类似物可能具有更高的治疗效用。
在此，我们报告了一种此类类似物的鉴定情况，该类似物是通过在他克莫司的C21乙基类似物子囊霉素（ASC）的C32位引入一个吲哚基团而合成得到的。在免疫抑制和毒性的啮齿动物模型中对吲哚基-ASC的生物活性谱进行了表征。
发现吲哚基-ASC在体外T细胞活化以及小鼠移植模型中表现出与他克莫司相当的免疫抑制效力，尽管吲哚基-ASC与细胞内FK506结合蛋白-12的结合量比他克莫司或ASC少约10倍。对吲哚基-ASC的进一步评估显示，在诱导体温过低（这一反应可能反映神经毒性）以及引起小鼠胃肠道转运改变方面，它的效力比他克莫司低三倍。此外，在大鼠中进行3周口服治疗后，吲哚基-ASC的肾毒性比他克莫司至少低两倍。
总体而言，这些数据表明在啮齿动物模型中，与他克莫司相比，吲哚基-ASC的治疗指数有适度但确定的改善。
