Structure–Activity Relationship Studies with Tetrahydroquinoline Analogs as EPAC Inhibitors
نویسندگان
چکیده
EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functional groups. The most potent EPAC inhibitor 12a exists as a mixture of inseparable E (major) and Z (minor) rotamers. The rotation about the N-formyl group indeed impacts the activity against EPAC.
منابع مشابه
Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac.
The cAMP-binding protein Epac is a therapeutic target for the treatment of various diseases such as cardiac hypertrophy and tumor invasion. This points out the importance to develop Epac inhibitors to better understand the involvement of these cAMP sensors in physiology and pathophysiology. Here, we have developed a functional fluorescence-based high-throughput assay with a Z' value around 0.7 ...
متن کاملNew Insight into the SAR of Pyrimido [4,5-b][1,4] Benzothiazines as 15-lipoxygenase Inhibitors
Objective(s): Recently we reported that the soybean 15-lipoxygenase (SLO) inhibitory activity of pyrimido[4,5-b][l,4]benzothiazines largely depends on the orientation of sulfur atom of thiazine core towards FeIII-OH in the active site pocket of the enzyme with subsequent oxidation of sulfur to sulfoxide. In this paper the results of a comparative study on the SLO inhibitory activities of the ...
متن کاملOpposing Roles of pka and epac in the cAMP-Dependent Regulation of Schwann Cell Proliferation and Differentiation
In Schwann cells (SCs), cyclic adenosine monophosphate (cAMP) not only induces differentiation into a myelinating SC-related phenotype, but also synergistically enhances the mitogenic action of growth factors such as neuregulin. To better understand the molecular mechanism by which cAMP exerts these apparently contradictory functions, we investigated the role of the two main effectors of cAMP, ...
متن کاملBiochemical and Pharmacological Characterizations of ESI-09 Based EPAC Inhibitors: Defining the ESI-09 “Therapeutic Window”
The cAMP signaling cascade is one of the most frequently targeted pathways for the development of pharmaceutics. A plethora of recent genetic and pharmacological studies suggest that exchange proteins directly activated by cAMP (EPACs) are implicated in multiple pathologies. Selective EPAC inhibitors have been recently developed. One specific inhibitor, ESI-09, has been shown to block EPAC acti...
متن کاملQSAR, Docking and Molecular Dynamics Studies on the Piperidone-grafted Mono- and Bis-spiro-oxindole-hexahydropyrrolizines as Potent Butyrylcholinesterase Inhibitors
ABSTRACT: Quantitative structure-activity relationship (QSAR) study on the piperidone-grafted mono- and bis-spirooxindole-hexahydropyrrolizines as potent butyrylcholinestrase (BuChE) inhibitors were carried out using statistical methods, molecular dynamics and molecular docking simulation. QSAR methodologies, including classification and regression tree (CART), multiple linear regression (MLR),...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره 8 شماره
صفحات -
تاریخ انتشار 2017