一系列新型吡唑并吡啶作为缺氧诱导因子-1α脯氨酰羟化酶抑制剂的设计与合成
Design and synthesis of a series of novel pyrazolopyridines as HIF-1alpha prolyl hydroxylase inhibitors.
作者信息
Warshakoon Namal C, Wu Shengde, Boyer Angelique, Kawamoto Richard, Renock Sean, Xu Kevin, Pokross Matthew, Evdokimov Artem G, Zhou Songtao, Winter Carol, Walter Richard, Mekel Marlene
机构信息
Procter and Gamble Pharmaceuticals Inc, 8700 Mason-Montgomery road, Mason, OH 45040, USA.
出版信息
Bioorg Med Chem Lett. 2006 Nov 1;16(21):5687-90. doi: 10.1016/j.bmcl.2006.08.017.
Recently resolved X-ray crystal structure of HIF-1alpha prolyl hydroxylase was used to design and develop a novel series of pyrazolopyridines as potent HIF-1alpha prolyl hydroxylase inhibitors. The activity of these compounds was determined in a human EGLN-1 assay. Structure-based design aided in optimizing the potency of the initial lead (2, IC(50) of 11 microM) to a potent (11l, 190 nM) EGLN-1 inhibitor. Several of these analogs were potent VEGF inducers in a cell-based assay. These pyrazolopyridines were also effective in stabilizing HIF-1alpha.
最近解析的低氧诱导因子-1α脯氨酰羟化酶的X射线晶体结构被用于设计和开发一系列新型吡唑并吡啶类化合物，作为有效的低氧诱导因子-1α脯氨酰羟化酶抑制剂。这些化合物的活性在人EGLN-1检测中得以确定。基于结构的设计有助于将最初的先导化合物（2，半数抑制浓度为11微摩尔）的效力优化至一种强效的（11l，190纳摩尔）EGLN-1抑制剂。其中一些类似物在基于细胞的检测中是强效的血管内皮生长因子诱导剂。这些吡唑并吡啶类化合物在稳定低氧诱导因子-1α方面也很有效。
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