Design, synthesis, and structure-activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors

Bioorganic & Medicinal Chemistry
Yorinobu YasudaHideaki Kakeya

Abstract

Hypoxia-inducible factor (HIF)-1 is well known as a promising target for cancer chemotherapy. By screening an in-house chemical library using a hypoxia-responsive luciferase reporter gene assay, we identified CLB-016 (1) containing 1-ethylpyrazole-3-carboxamide as a HIF-1 inhibitor (IC50=19.1μM). In a subsequent extensive structure-activity relationship (SAR) study, we developed compound 11Ae with an IC50 value of 8.1μM against HIF-1-driven luciferase activity. Compounds 1 and 11Ae were shown to significantly suppress the HIF-1-mediated hypoxia response, including carbonic anhydrase IX (CAIX) gene expression and migration of human sarcoma HT1080 cells. These results revealed 1-ethylpyrazole-3-carboxamide as a novel scaffold to develop promising anti-cancer drugs targeting the HIF-1 signaling pathway.

References

Sep 18, 2003·Nature Reviews. Cancer·Gregg L Semenza
Mar 1, 2010·Expert Opinion on Drug Discovery·Michael J Waring

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Citations

Feb 18, 2016·Expert Opinion on Therapeutic Patents·Hyun Seung BanHiroyuki Nakamura
Jan 17, 2016·Biochemical and Biophysical Research Communications·Mohammad TariqMinoru Yoshida
Sep 10, 2015·The Journal of Antibiotics·Hideaki KakeyaHiroyuki Osada
Sep 19, 2019·Chemical Communications : Chem Comm·Nobuaki TakahashiHideaki Kakeya
Apr 27, 2021·Future Medicinal Chemistry·Po-Chen ChuChih-Shiang Chang
Aug 1, 2021·The Journal of Antibiotics·Hiroaki Ikeda, Hideaki Kakeya
Aug 8, 2021·Cancers·Gemma Di PompoSofia Avnet

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