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

Na Ye, Yingmin Zhu, Haijun Chen, Zhiqing Liu, Fang C. Mei, Christopher Wild, Haiying Chen, Xiaodong Cheng, Jia Zhou

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6033-6047
Number of pages15
JournalJournal of Medicinal Chemistry
Volume58
Issue number15
DOIs
StatePublished - Jul 17 2015

Fingerprint

Cyanides
Structure-Activity Relationship
Proteins
Physiological Phenomena
Isoxazoles
Guanine Nucleotide Exchange Factors
Second Messenger Systems
azastene
Pharmacology

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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. / Ye, Na; Zhu, Yingmin; Chen, Haijun; Liu, Zhiqing; Mei, Fang C.; Wild, Christopher; Chen, Haiying; Cheng, Xiaodong; Zhou, Jia.

In: Journal of Medicinal Chemistry, Vol. 58, No. 15, 17.07.2015, p. 6033-6047.

Research output: Contribution to journalArticle

@article{7c4deac87abd42bf8f6b18276bf01217,
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.",
author = "Na Ye and Yingmin Zhu and Haijun Chen and Zhiqing Liu and Mei, {Fang C.} and Christopher Wild and Haiying Chen and Xiaodong Cheng and Jia Zhou",
year = "2015",
month = "7",
day = "17",
doi = "10.1021/acs.jmedchem.5b00635",
language = "English (US)",
volume = "58",
pages = "6033--6047",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "15",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=84939198299&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84939198299&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b00635

DO - 10.1021/acs.jmedchem.5b00635

M3 - Article

C2 - 26151319

AN - SCOPUS:84939198299

VL - 58

SP - 6033

EP - 6047

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 15

ER -