Identification of novel 2-(benzo[d]isoxazol-3-yl)-2-oxo-N-phenylacetohydrazonoyl cyanide analoguesas potent EPAC antagonists

Na Ye, Yingmin Zhu, Zhiqing Liu, Fang C. Mei, Haiying Chen, Pingyuan Wang, Xiaodong Cheng, Jia Zhou

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Two series of novel EPAC antagonists are designed, synthesized and evaluated in an effort to develop diversified analogues based on the scaffold of the previously identified high-throughput (HTS) hit 1 (ESI-09). Further SAR studies reveal that the isoxazole ring A of 1 can tolerate chemical modifications with either introduction of flexible electron-donating substitutions or structurally restrictedly fusing with a phenyl ring, leading to identification of several more potent and diversified EPAC antagonists (e.g., 10 (NY0617), 14 (NY0460), 26 (NY0725), 32 (NY0561), and 33 (NY0562)) with low micromolar inhibitory activities. Molecular docking studies on compounds 10 and 33 indicate that these two series of compounds bind at a similar site with substantially different interactions with the EPAC proteins. The findings may serve as good starting points for the development of more potent EPAC antagonists as valuable pharmacological probes or potential drug candidates.

Original languageEnglish (US)
Pages (from-to)62-71
Number of pages10
JournalEuropean journal of medicinal chemistry
StatePublished - 2017


  • Antagonist
  • EPAC
  • Exchange proteins directly activated by cAMP
  • Molecular docking

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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