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Jose A Morales-Garcia, Victor Echeverry-Alzate, Sandra Alonso-Gil, Marina Sanz-SanCristobal, Jose A Lopez-Moreno, Carmen Gil, Ana Martinez, Angel Santos, Ana Perez-Castillo
The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling intracellular levels of cyclic adenosine 3',5'-monophosphate in the immune and central nervous system. We have previously shown that inhibitors of this enzyme are potent neuroprotective and anti-inflammatory agents. In addition we also demonstrated that PDE7 inhibition induces endogenous neuroregenerative processes towards a dopaminergic phenotype. Here, we show that PDE7 inhibition controls stem cell expansion in the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the subventricular zone (SVZ) in the adult rat brain...
August 19, 2016: Stem Cells
Chenjia Xu, Arlene R Wyman, Manal A Alaamery, Shannon A Argueta, F Douglas Ivey, John A Meyers, Adam Lerner, Tricia H Burdo, Timothy Connolly, Charles S Hoffman, Thomas C Chiles
We have used a high throughput small molecule screen, using a fission yeast-based assay, to identify novel phosphodiesterase 7 (PDE7) inhibitors. One of the most effective hit compounds was BC12, a barbituric acid-based molecule that exhibits unusually potent immunosuppressive and immunomodulatory actions on T lymphocyte function, including inhibition of T cell proliferation and IL-2 cytokine production. BC12 treatment confers a >95% inhibition of IL-2 secretion in phytohaemagglutinin (PHA) plus phorbol-12-myristate-13-acetate (PMA) stimulated Jurkat T cells...
September 2016: International Immunopharmacology
Yung-Fong Tsai, Huang-Ping Yu, Pei-Jen Chung, Yann-Lii Leu, Liang-Mou Kuo, Chun-Yu Chen, Tsong-Long Hwang
Oxidative stress caused by neutrophils is an important pathogenic factor in trauma/hemorrhagic (T/H)-induced acute lung injury (ALI). Osthol, a natural coumarin found in traditional medicinal plants, has therapeutic potential in various diseases. However, the pharmacological effects of osthol in human neutrophils and its molecular mechanism of action remain elusive. In this study, our data showed that osthol potently inhibited the production of superoxide anion (O2(•-)) and reactive oxidants derived therefrom as well as expression of CD11b in N-formylmethionylleucylphenylalanine (FMLP)-activated human neutrophils...
December 2015: Free Radical Biology & Medicine
David Thomae, Stijn Servaes, Naiara Vazquez, Leonie Wyffels, Stefanie Dedeurwaerdere, Pieter Van der Veken, Jurgen Joossens, Koen Augustyns, Sigrid Stroobants, Steven Staelens
INTRODUCTION: Phosphodiesterase 7 (PDE7) hydrolyzes selectively cyclic adenosine monophosphate (cAMP) which is an intracellular second messenger. PDE7 is expressed by 2 genes which are both present in the brain. To date there is no radiotracer for PDE7 imaging described and detection of PDE7 has only been performed by ex vivo techniques. In this report we describe the radiosynthesis of a novel fluorine-18 labeled radiotracer for PDE7 as well as the in vivo evaluation in mice to verify whether it has potential for imaging of PDE7 in the brain...
December 2015: Nuclear Medicine and Biology
Hongli Dong, Kevin P Claffey, Stefan Brocke, Paul M Epstein
Almost all deaths from breast cancer arise from metastasis of the transformed cells to other sites in the body. Hence, uncovering a means of inhibiting breast cancer cell migration would provide a significant advance in the treatment of this disease. Stimulation of the cAMP signaling pathway has been shown to inhibit migration and motility of a number of cell types. A very effective way of selectively stimulating cAMP signaling is through inhibition of cyclic nucleotide phosphodiesterases (PDEs). Therefore, we examined full expression profiles of all known PDE genes at the mRNA and protein levels in four human breast cancer cell lines and eight patients' breast cancer tissues...
July 2015: Breast Cancer Research and Treatment
L Mestre, M Redondo, F J Carrillo-Salinas, J A Morales-García, S Alonso-Gil, A Pérez-Castillo, C Gil, A Martínez, C Guaza
BACKGROUND AND PURPOSE: cAMP plays an important role in the transduction of signalling pathways involved in neuroprotection and immune regulation. Control of the levels of this nucleotide by inhibition of cAMP-specific PDEs such as PDE7 may affect the pathological processes of neuroinflammatory diseases like multiple sclerosis (MS). In the present study, we evaluated the therapeutic potential of the selective PDE7 inhibitor, TC3.6, in a model of primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS...
September 2015: British Journal of Pharmacology
Jose A Morales-Garcia, Sandra Alonso-Gil, Carmen Gil, Ana Martinez, Angel Santos, Ana Perez-Castillo
UNLABELLED: Parkinson's disease is characterized by a loss of dopaminergic neurons in a specific brain region, the ventral midbrain. Parkinson's disease is diagnosed when approximately 50% of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) have degenerated and the others are already affected by the disease. Thus, it is conceivable that all therapeutic strategies, aimed at neuroprotection, start too late. Therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs with disease-modifying properties...
June 2015: Stem Cells Translational Medicine
Yusuke Endo, Kentaro Kawai, Takeshi Asano, Seiji Amano, Yoshihito Asanuma, Keisuke Sawada, Yuuta Onodera, Noriko Ueo, Nobuaki Takahashi, Yo Sonoda, Noriyuki Kamei, Tetsumi Irie
A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model...
May 1, 2015: Bioorganic & Medicinal Chemistry Letters
T S Petersen, S G Kristensen, J V Jeppesen, M L Grøndahl, M L Wissing, K T Macklon, C Y Andersen
The concentration of the important second messenger cAMP is regulated by phosphodiesterases (PDEs) and hence an attractive drug target. However, limited human data are available about the PDEs in the ovary. The aim of the present study was to describe and characterise the PDEs in the human ovary. Results were obtained by analysis of mRNA microarray data from follicles and granulosa cells (GCs), combined RT-PCR and enzymatic activity analysis in GCs, immunohistochemical analysis of ovarian sections and by studying the effect of PDE inhibitors on progesterone production from cultured GCs...
March 5, 2015: Molecular and Cellular Endocrinology
Clive P Page
Xanthines like theophylline have long been recognised as being effective drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD). They are of interest as they possess both anti-inflammatory and bronchodilator activity in the same molecule. Since the discovery of phosphodiesterases (PDEs) in the late 1950s, it has been suggested that xanthines work, in part, by acting as non-selective PDE inhibitors. However, it has also been suggested that the ability of xanthines to non-selectively inhibit PDEs contributes to their many unwanted side effects, thus limiting their use since the arrival of inhaled drugs with more favourable safety profiles...
2014: International Archives of Allergy and Immunology
Yusuke Endo, Kentaro Kawai, Takeshi Asano, Seiji Amano, Yoshihito Asanuma, Keisuke Sawada, Keiji Ogura, Naoya Nagata, Noriko Ueo, Nobuaki Takahashi, Yo Sonoda, Noriyuki Kamei
The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility...
February 1, 2015: Bioorganic & Medicinal Chemistry Letters
Jose A Morales-Garcia, Diana Aguilar-Morante, Elena Hernandez-Encinas, Sandra Alonso-Gil, Carmen Gil, Ana Martinez, Angel Santos, Ana Perez-Castillo
Different studies have suggested that the nucleotide cyclic adenosine 3', 5'-monophosphate can actively play an important role as a neuroprotective and anti-inflammatory agent after a brain injury. The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling specifically the intracellular levels of cyclic adenosine 3', 5'-monophosphate in the immune and central nervous systems. Therefore, this enzyme could play an important role in brain inflammation and neurodegeneration. In this regard, using different chemical inhibitors of PDE7 we have demonstrated their neuroprotective and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease (PD)...
February 2015: Neurobiology of Aging
Kentaro Kawai, Yusuke Endo, Takeshi Asano, Seiji Amano, Keisuke Sawada, Noriko Ueo, Nobuaki Takahashi, Yo Sonoda, Mika Nagai, Noriyuki Kamei, Naoya Nagata
The discovery of a new series of potent phosphodiesterase 7 (PDE7) inhibitors is described. Novel thieno[3,2-d]pyrimidin-4(3H)-one hit compounds were identified from our chemical library. Preliminary modifications of the hit compounds were performed, resulting in the discovery of a fragment-sized compound (10) with highly improved ligand efficiency. Compound design was guided by structure-activity relationships and computational modeling. The 6-substituted derivatives of the thienopyrimidinone showed diminished activity and enzyme selectivity...
December 11, 2014: Journal of Medicinal Chemistry
Ana Martinez, Carmen Gil
INTRODUCTION: PDEs are key enzymes in the adenosine and guanosine cyclic nucleotides (cAMP and cGMP) signaling cascade. Their inhibition increases cyclic nucleotide levels inside the cell. Thus, pharmacological modulation of PDE activity can have profound effects on the function of cells and organ systems throughout the body. AREAS COVERED: Among the large PDE families, only PDE4, PDE7 and PDE8 are cAMP-specific hydrolyzing enzymes. cAMP is an important second messenger not only by its involvement in a vast number of physiological processes but also by activation of protein kinase A, exchange protein activated by cAMP (Epac) and cAMP response element-binding (CREB) or cyclic nucleotide-gated channels...
December 2014: Expert Opinion on Therapeutic Patents
Ana M García, José Brea, Jose A Morales-García, Daniel I Perez, Alejandro González, Sandra Alonso-Gil, Irene Gracia-Rubio, Clara Ros-Simó, Santiago Conde, María Isabel Cadavid, María Isabel Loza, Ana Perez-Castillo, Olga Valverde, Ana Martinez, Carmen Gil
A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work...
October 23, 2014: Journal of Medicinal Chemistry
P R A Heckman, C Wouters, J Prickaerts
Phosphodiesterase inhibitors (PDE-Is) enhance cAMP and/or cGMP signaling via reducing the degradation of these cyclic nucleotides. Since both cAMP and cGMP signaling are essential in a variety of cellular functions, including neuroplasticity and neuroprotection, PDE-Is are receiving increased attention as possible targets for treatment of age-related cognitive decline as well as Alzheimer's disease (AD). In this review we will give a translational overview of the preclinical and clinical data on PDE-Is and cognition enhancement focusing on aging and AD...
2015: Current Pharmaceutical Design
Ana I Sánchez, Ricardo Meneses, José M Mínguez, Araceli Núñez, Rafael R Castillo, Fabiana Filace, Carolina Burgos, Juan J Vaquero, Julio Álvarez-Builla, Alvaro Cortés-Cabrera, Federico Gago, Emma Terricabras, Víctor Segarra
A series of novel thienopyrimidin-4-amines have been synthesized and evaluated as phosphodiesterase (PDE) inhibitors. A rationale for the observed selectivity against PDE7 has been obtained from molecular modelling studies on the most active compounds.
June 28, 2014: Organic & Biomolecular Chemistry
Jose A Morales-Garcia, Valle Palomo, Miriam Redondo, Sandra Alonso-Gil, Carmen Gil, Ana Martinez, Ana Perez-Castillo
Chronic neuroinflammation has been increasingly recognized as a primary mechanism underlying acute brain injury and neurodegenerative diseases. Enhanced expression of diverse pro-inflammatory agents in glial cells has been shown to contribute to the cell death that takes place in these disorders. Previous data from our group have shown that different inhibitors of the cyclic adenosine monophosphate (cAMP) specific phosphodiesterase 7 (PDE7) and glycogen synthase kinase-3 (GSK-3) enzymes are potent anti-inflammatory agents in different models of brain injury...
March 19, 2014: ACS Chemical Neuroscience
Miriam Redondo, Ignacio Soteras, José Brea, Alejandro González-García, María Isabel Cadavid, María Isabel Loza, Ana Martinez, Carmen Gil, Nuria E Campillo
The last findings of our group by using chemical genetic approaches have shown that PDE7 is an interesting target in neurodegenerative diseases. The following step in this travel to unravel PDE7 is the design of more selective inhibitors. In this sense we have proposed to perform an analysis of PDE7 surface to identify possible allosteric sites following by a docking study of different PDE7 inhibitors synthesized by our group. Thanks to these studies we have proved the existence of allosteric sites in PDE7 and we have been able to explain the binding modes of the employed PDE7 inhibitors...
2013: European Journal of Medicinal Chemistry
Didem Demirbas, Arlene R Wyman, Masami Shimizu-Albergine, Ozgur Cakici, Joseph A Beavo, Charles S Hoffman
A cell-based high-throughput screen (HTS) was developed to detect phosphodiesterase 8 (PDE8) and PDE4/8 combination inhibitors. By replacing the Schizosaccharomyces pombe PDE gene with the murine PDE8A1 gene in strains lacking adenylyl cyclase, we generated strains whose protein kinase A (PKA)-stimulated growth in 5-fluoro orotic acid (5FOA) medium reflects PDE8 activity. From our previously-identified PDE4 and PDE7 inhibitors, we identified a PDE4/8 inhibitor that allowed us to optimize screening conditions...
2013: PloS One
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