TY - JOUR
T1 - Structure-Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N′-phenyl-acetohydrazonoyl Cyanide Analogues
T2 - Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists
AU - Ye, Na
AU - Zhu, Yingmin
AU - Chen, Haijun
AU - Liu, Zhiqing
AU - Mei, Fang C.
AU - Wild, Christopher
AU - Chen, Haiying
AU - Cheng, Xiaodong
AU - Zhou, Jia
N1 - Publisher Copyright:
© 2015 American Chemical Society.
PY - 2015/7/17
Y1 - 2015/7/17
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.5b00635
DO - 10.1021/acs.jmedchem.5b00635
M3 - Article
C2 - 26151319
AN - SCOPUS:84939198299
SN - 0022-2623
VL - 58
SP - 6033
EP - 6047
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 15
ER -