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

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

Yong Rae Hong ¹, Hyun Tae Kim ², Seonggu Ro ³, Joong Myung Cho ², Sang Hwi Lee ⁴, In Su Kim ⁴, Young Hoon Jung ⁵

Affiliations

1 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.
2 CrystalGenomics, Inc., 5F, Tower A, Korea Bio Park 694-1, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.
3 CrystalGenomics, Inc., 5F, Tower A, Korea Bio Park 694-1, Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea. Electronic address: sgro@cgxinc.com.
4 School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
5 School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: yhjung@skku.edu.

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

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.

Keywords

EPO; HIF-PHs (PHDs); Inhibitor; Stabilizer.

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