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新型 2-[2-(3-羟基-2-吡啶基)-噻唑-4-基]-乙酰胺衍生物作为低氧诱导因子脯氨酰 4-羟化酶抑制剂的发现;SAR、合成与建模评价。

Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation.

机构信息

CrystalGenomics, Inc., 5F, Tower A, Korea Bio Park 694-1, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.

CrystalGenomics, Inc., 5F, Tower A, Korea Bio Park 694-1, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.

出版信息

Bioorg Med Chem Lett. 2014 Jul 15;24(14):3142-5. doi: 10.1016/j.bmcl.2014.05.003. Epub 2014 May 15.

DOI:10.1016/j.bmcl.2014.05.003
PMID:24894560
Abstract

The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analogs containing the new scaffolds. In addition, the structure-activity relationship (SAR) of the 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives and their biological activities were reported. The complex structure of compound 18 with PHD2 was also obtained for the purpose of more efficient lead optimization.

摘要

描述了 2-[2-(3-羟基-吡啶-2-基)-噻唑-4-基]-乙酰胺类似物的设计、合成和抑制低氧诱导因子脯氨酰 4-羟化酶（PHD）的能力。这些类似物揭示了两种新型支架作为 PHD2 抑制剂。开发了合成路线来制备含有新支架的类似物。此外，还报道了 2-[2-(3-羟基-吡啶-2-基)-噻唑-4-基]-乙酰胺衍生物的构效关系（SAR）及其生物活性。还获得了化合物 18 与 PHD2 的复合物结构，目的是更有效地进行先导优化。

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