title: Structure-Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists.
abstract: Exchange proteins directly activated by cAMP (EPAC) as guanine nucleotide exchange factors mediate the effects of the pivotal second messenger cAMP, thereby regulating a wide variety of intracellular physiological and pathophysiological processes. A series of novel 2-(isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl cyanide EPAC antagonists was synthesized and evaluated in an effort to optimize properties of the previously identified high-throughput (HTS) hit 1 (ESI-09). Structure-activity relationship (SAR) analysis led to the discovery of several more active EPAC antagonists (e.g., 22 (HJC0726), 35 (NY0123), and 47 (NY0173)) with low micromolar inhibitory activity. These inhibitors may serve as valuable pharmacological probes to facilitate our efforts in elucidating the biological functions of EPAC and developing potential novel therapeutics against human diseases. Our SAR results have also revealed that further modification at the 3-, 4-, and 5-positions of the phenyl ring as well as the 5-position of the isoxazole moiety may allow for the development of more potent EPAC antagonists.
authors.affiliation: †Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
authors.forename: Na
authors.initials: N
authors.lastname: Ye
authors.affiliation: ‡Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 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, Texas 77555, United States.
authors.forename: Haijun
authors.initials: H
authors.lastname: Chen
authors.affiliation: †Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: ‡Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 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, Texas 77555, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Wild
authors.affiliation: †Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
authors.forename: Haiying
authors.initials: H
authors.lastname: Chen
authors.affiliation: ‡Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030, United States.
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, Texas 77555, United States.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
mesh_terms: D003486:Cyanides / Q000737:chemistry*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors*; D006835:Hydrazones / Q000737:chemistry*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D003486:Cyanides; D006835:Hydrazones; D000242:Cyclic AMP