title: Identification of novel 2-(benzo[d]isoxazol-3-yl)-2-oxo-N-phenylacetohydrazonoyl cyanide analoguesas potent EPAC antagonists.
abstract: 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.
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States; Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
authors.forename: Na
authors.initials: N
authors.lastname: Ye
authors.affiliation: Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, TX 77030, United States.
authors.forename: Yingmin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, TX 77030, United States.
authors.forename: Fang C
authors.initials: FC
authors.lastname: Mei
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States.
authors.forename: Pingyuan
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The University of Texas Health Science Center, Houston, TX 77030, United States. Electronic address: xiaodong.cheng@uth.tmc.edu.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, United States. Electronic address: jizhou@utmb.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
mesh_terms: D000818:Animals; D003486:Cyanides / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000737:chemistry* / Q000494:pharmacology*; D007555:Isoxazoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: C579558:3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile; D003486:Cyanides; D020662:Guanine Nucleotide Exchange Factors; D006835:Hydrazones; D007555:Isoxazoles; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human
keywords: Antagonist; EPAC; Exchange proteins directly activated by cAMP; Molecular docking