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Literature DB >> 27190593

Functionalized N,N-Diphenylamines as Potent and Selective EPAC2 Inhibitors.

Christopher T Wild¹, Yingmin Zhu², Ye Na¹, Fang Mei², Marcus A Ynalvez¹, Haiying Chen¹, Xiaodong Cheng², Jia Zhou¹.

Abstract

N,N-Diphenylamines were discovered as potent and selective EPAC2 inhibitors. A study was conducted to determine the structure-activity relationships in a series of inhibitors of which several compounds displayed submicromolar potencies. Selectivity over the related EPAC1 protein was also demonstrated. Computational modeling reveals an allosteric site that is distinct from the cAMP binding domain shared by both EPAC isoforms, providing a theory with regards to subtype selectivity.

Entities: Chemical Gene

Keywords: Buchwald−Hartwig amination; Exchange proteins directly activated by cAMP (EPAC) inhibitors; diphenylamines; structure−activity relationship

Year: 2016 PMID： 27190593 PMCID： PMC4867506 DOI： 10.1021/acsmedchemlett.5b00477

Source DB: PubMed Journal: ACS Med Chem Lett ISSN： 1948-5875 Impact factor: 4.345

33 in total

1. Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs.

Authors: J de Rooij; H Rehmann; M van Triest; R H Cool; A Wittinghofer; J L Bos
Journal: J Biol Chem Date: 2000-07-07 Impact factor: 5.157

2. Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus.

Authors: Xinrong Tao; Feng Mei; Anurodh Agrawal; Clarence J Peters; Thomas G Ksiazek; Xiaodong Cheng; Chien-Te K Tseng
Journal: J Virol Date: 2014-01-22 Impact factor: 5.103

3. 5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP.

Authors: Haijun Chen; Tamara Tsalkova; Fang C Mei; Yaohua Hu; Xiaodong Cheng; Jia Zhou
Journal: Bioorg Med Chem Lett Date: 2012-04-26 Impact factor: 2.823

4. Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors.

Authors: Loren M Brown; Kathleen E Rogers; Nakon Aroonsakool; J Andrew McCammon; Paul A Insel
Journal: J Biol Chem Date: 2014-09-02 Impact factor: 5.157

5. Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo.

Authors: Muayad Almahariq; Celia Chao; Fang C Mei; Mark R Hellmich; Igor Patrikeev; Massoud Motamedi; Xiaodong Cheng
Journal: Mol Pharmacol Date: 2014-11-10 Impact factor: 4.436

6. Isoform-specific antagonists of exchange proteins directly activated by cAMP.

Authors: Tamara Tsalkova; Fang C Mei; Sheng Li; Oleg G Chepurny; Colin A Leech; Tong Liu; George G Holz; Virgil L Woods; Xiaodong Cheng
Journal: Proc Natl Acad Sci U S A Date: 2012-10-22 Impact factor: 11.205

7. Efficient Synthesis of ESI-09, A Novel Non-cyclic Nucleotide EPAC Antagonist.

Authors: Haijun Chen; Chunyong Ding; Christopher Wild; Huiling Liu; Tianzhi Wang; Mark A White; Xiaodong Cheng; Jia Zhou
Journal: Tetrahedron Lett Date: 2013-03-20 Impact factor: 2.415

Review 8. Cyclic AMP sensor EPAC proteins and energy homeostasis.

Authors: Muayad Almahariq; Fang C Mei; Xiaodong Cheng
Journal: Trends Endocrinol Metab Date: 2013-11-12 Impact factor: 12.015

9. Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy.

Authors: Coskun Ulucan; Xu Wang; Erdene Baljinnyam; Yunzhe Bai; Satoshi Okumura; Motohiko Sato; Susumu Minamisawa; Shinichi Hirotani; Yoshihiro Ishikawa
Journal: Am J Physiol Heart Circ Physiol Date: 2007-06-08 Impact factor: 4.733

10. Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window".

Authors: Yingmin Zhu; Haijun Chen; Stephen Boulton; Fang Mei; Na Ye; Giuseppe Melacini; Jia Zhou; Xiaodong Cheng
Journal: Sci Rep Date: 2015-03-20 Impact factor: 4.379

10 in total

Review 1. Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.

Authors: William G Robichaux; Xiaodong Cheng
Journal: Physiol Rev Date: 2018-04-01 Impact factor: 37.312

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

Authors: Na Ye; Yingmin Zhu; Zhiqing Liu; Fang C Mei; Haiying Chen; Pingyuan Wang; Xiaodong Cheng; Jia Zhou
Journal: Eur J Med Chem Date: 2017-04-04 Impact factor: 6.514

3. Structure-activity relationships of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs).

Authors: Zhiqing Liu; Yingmin Zhu; Haiying Chen; Pingyuan Wang; Fang C Mei; Na Ye; Xiaodong Cheng; Jia Zhou
Journal: Bioorg Med Chem Lett Date: 2017-10-25 Impact factor: 2.823

Functionalized N,N-Diphenylamines as Potent and Selective EPAC2 Inhibitors.

1. Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs.

2. Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus.

3. 5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP.

4. Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors.

5. Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo.

6. Isoform-specific antagonists of exchange proteins directly activated by cAMP.

7. Efficient Synthesis of ESI-09, A Novel Non-cyclic Nucleotide EPAC Antagonist.

Review 8. Cyclic AMP sensor EPAC proteins and energy homeostasis.

9. Developmental changes in gene expression of Epac and its upregulation in myocardial hypertrophy.

10. Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window".

Review 1. Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.

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

3. Structure-activity relationships of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as novel antagonists of exchange proteins directly activated by cAMP (EPACs).

Review 4. The Potential of a Novel Class of EPAC-Selective Agonists to Combat Cardiovascular Inflammation.

Review 5. Exchange proteins directly activated by cAMP (EPACs): Emerging therapeutic targets.

Review 6. Targeting the Small GTPase Superfamily through Their Regulatory Proteins.

7. Overexpression of EPAC2 reduces the invasion of glioma cells via MMP-2.

8. Exchange Protein Directly Activated by cAMP 2 Enhances Respiratory Syncytial Virus-Induced Pulmonary Disease in Mice.

9. Diarylamine-Guided Carboxamide Derivatives: Synthesis, Biological Evaluation, and Potential Mechanism of Action.

10. Broad Impact of Exchange Protein Directly Activated by cAMP 2 (EPAC2) on Respiratory Viral Infections.