Praecis Pharmaceuticals, Inc., Waltham, MA 02451-1420, USA.
J Med Chem. 2009 Dec 24;52(24):8047-56. doi: 10.1021/jm901260k.
Inhibition of methionine aminopeptidase-2 (MetAP2) represents a novel approach to antiangiogenic therapy. We describe the synthesis and activity of fumagillin analogues that address the pharmacokinetic and safety liabilities of earlier candidates in this compound class. Two-step elaboration of fumagillol with amines yielded a diverse series of carbamates at C6 of the cyclohexane spiroepoxide. The most potent of these compounds exhibited subnanomolar inhibition of cell proliferation in HUVEC and BAEC assays. Although a range of functionalities were tolerated at this position, alpha-trisubstituted amines possessed markedly decreased inhibitory activity, and this could be rationalized by modeling based on the known fumagillin-MetAP2 crystal structure. The lead compound resulting from these studies, (3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-methyl-3-(3-methylbut-2-enyl)oxiran-2-yl)-1-oxaspiro[2.5]octan-6-yl (R)-1-amino-3-methyl-1-oxobutan-2-ylcarbamate, (PPI-2458), demonstrated an improved pharmacokinetic profile relative to the earlier clinical candidate TNP-470, and has advanced into phase I clinical studies in non-Hodgkin's lymphoma and solid cancers.
抑制蛋氨酸氨肽酶-2（MetAP2）代表了一种新的抗血管生成治疗方法。我们描述了福米基林类似物的合成和活性，这些类似物解决了该化合物类别的早期候选药物在药代动力学和安全性方面的问题。福米基醇与胺的两步精心设计，在环己烷螺环氧化物的 C6 位生成了一系列不同的氨基甲酸酯。这些化合物中最有效的一种在 HUVEC 和 BAEC 测定中表现出亚纳摩尔级别的细胞增殖抑制活性。尽管在此位置可以容忍多种官能团，但α-三取代胺的抑制活性明显降低，这可以通过基于已知福米基林-MetAP2 晶体结构的建模来合理化。从这些研究中得到的先导化合物是（3R,4S,5S,6R）-5-甲氧基-4-((2R,3R)-2-甲基-3-(3-甲基-2-丁烯基）环氧乙烷-2-基）-1-氧杂螺[2.5]辛烷-6-基（R）-1-氨基-3-甲基-1-氧代丁-2-基氨基甲酸酯（PPI-2458），与早期的临床候选药物 TNP-470 相比，具有改善的药代动力学特征，并已进入非霍奇金淋巴瘤和实体癌的 I 期临床研究。
