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Ana Santos de Medeiros, Arlene R Wyman, Manal A Alaamery, Christina Allain, F Douglas Ivey, Lili Wang, Hai Le, James P Morken, Alawi Habara, Cuong Le, Shuaiying Cui, Adam Lerner, Charles S Hoffman
We previously constructed a collection of fission yeast strains that express various mammalian cyclic nucleotide phosphodiesterases (PDEs) and developed a cell-based high throughput screen (HTS) for small molecule PDE inhibitors. Here we describe a compound, BC54, that is a selective inhibitor of enzymes from the cAMP-specific PDE4 and PDE7 families. Consistent with the biological effect of other PDE4 and PDE7 inhibitors, BC54 displays potent anti-inflammatory properties and is superior to a combination of rolipram (a PDE4 inhibitor) and BRL50481 (a PDE7A inhibitor) for inducing apoptosis in chronic lymphocytic leukemia (CLL) cells...
December 2017: Cellular Signalling
Kensuke Nishi, Hao Luo, Shuhei Ishikura, Keiko Doi, Yuri Iwaihara, Lauren Wills, George S Baillie, Toshifumi Sakata, Senji Shirasawa, Toshiyuki Tsunoda
BACKGROUND/AIM: We previously reported the crucial roles of oncogenic Kirsten rat sarcoma viral oncogene homologue (KRAS) in inhibiting apoptosis and disrupting cell polarity via the regulation of phosphodiesterase type 4B2 (PDE4B2) expression in human colorectal cancer (CRC) HCT116 cells in a three-dimensional culture (3DC). Here, we evaluated the effects of apremilast, a selective PDE4 inhibitor, on luminal apoptosis in 3DC and nude mice assay using HKe3 human CRC cells stably expressing wild-type (wt)PDE4B2 (HKe3-wtPDE4B2), mutant (mt)PDE4B2 (kinase dead) (HKe3-wtKRAS), wtKRAS (HKe3-wtKRAS) and mtKRAS (HKe3-mtKRAS)...
July 2017: Anticancer Research
Nicole M Wilson, Mark E Gurney, W Dalton Dietrich, Coleen M Atkins
Traumatic brain injury (TBI) initiates a deleterious inflammatory response that exacerbates pathology and worsens outcome. This inflammatory response is partially mediated by a reduction in cAMP and a concomitant upregulation of cAMP-hydrolyzing phosphodiesterases (PDEs) acutely after TBI. The PDE4B subfamily, specifically PDE4B2, has been found to regulate cAMP in inflammatory cells, such as neutrophils, macrophages and microglia. To determine if PDE4B regulates inflammation and subsequent pathology after TBI, adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury (2 ± 0...
2017: PloS One
Hao Huang, Qian Hong, Hong-Ling Tan, Cheng-Rong Xiao, Yue Gao
AIM: Phosphodiesterase 4 (PDE4) isozymes are involved in different functions, depending on their patterns of distribution in the brain. The PDE4 subtypes are distributed in different inflammatory cells, and appear to be important regulators of inflammatory processes. In this study we examined the effects of ferulic acid (FA), a plant component with strong anti-oxidant and anti-inflammatory activities, on lipopolysaccharide (LPS)-induced up-regulation of phosphodiesterase 4B (PDE4B) in PC12 cells, which in turn regulated cellular cAMP levels and the cAMP/cAMP response element binding protein (CREB) pathway in the cells...
December 2016: Acta Pharmacologica Sinica
David J Titus, Nicole M Wilson, Julie E Freund, Melissa M Carballosa, Kevin E Sikah, Concepcion Furones, W Dalton Dietrich, Mark E Gurney, Coleen M Atkins
UNLABELLED: Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI...
July 6, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Chen Dong, Charlotte Virtucio, Olga Zemska, Grober Baltazar, Yasheen Zhou, Diogo Baia, Shannon Jones-Iatauro, Holly Sexton, Shamra Martin, Joshua Dee, Yvonne Mak, Maliwan Meewan, Fernando Rock, Tsutomu Akama, Kurt Jarnagin
Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme...
September 2016: Journal of Pharmacology and Experimental Therapeutics
Nicole M Wilson, David J Titus, Anthony A Oliva, Concepcion Furones, Coleen M Atkins
Traumatic brain injury (TBI) results in significant impairments in hippocampal synaptic plasticity. A molecule critically involved in hippocampal synaptic plasticity, 3',5'-cyclic adenosine monophosphate, is downregulated in the hippocampus after TBI, but the mechanism that underlies this decrease is unknown. To address this question, we determined whether phosphodiesterase (PDE) expression in the hippocampus is altered by TBI. Young adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury...
2016: Frontiers in Systems Neuroscience
Hao Huang, Zeng-Chun Ma, Yu-Guang Wang, Qian Hong, Hong-Ling Tan, Cheng-Rong Xiao, Qian-De Liang, Xiang-Lin Tang, Yue Gao
OBJECTIVE: Phosphodiesterase (PDE) plays an important role in the pathogenesis of Alzheimer's disease (AD). Ferulic acid (FA) has a therapeutic benefit in the treatment of AD. We investigated whether this therapeutic effect is based on the modulation of the PDE/cyclic adenosine monophosphate (cAMP) pathway. In the present study, we investigated whether FA could abrogate Aβ25-35- and lipopolysaccharide-induced cellular damage. MATERIALS AND METHODS: Cell viability, superoxide production, and the levels of inflammatory factors were investigated...
October 2015: International Journal of Clinical Pharmacology and Therapeutics
Chiara Brullo, Matteo Massa, Carla Villa, Roberta Ricciarelli, Daniela Rivera, Maria Adelaide Pronzato, Ernesto Fedele, Elisabetta Barocelli, Simona Bertoni, Lisa Flammini, Olga Bruno
A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue...
July 1, 2015: Bioorganic & Medicinal Chemistry
Seiko Susuki-Miyata, Masanori Miyata, Byung-Cheol Lee, Haidong Xu, Hirofumi Kai, Chen Yan, Jian-Dong Li
Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of PDE4B up-regulation, which could be counterproductive for suppressing inflammation. Thus, understanding how PDE4B is up-regulated in the context of the complex pathogenesis and medications of COPD may help improve the efficacy and possibly ameliorate the tolerance of roflumilast...
April 7, 2015: Proceedings of the National Academy of Sciences of the United States of America
Chiara Brullo, Matteo Massa, Massimo Rocca, Chiara Rotolo, Sara Guariento, Daniela Rivera, Roberta Ricciarelli, Ernesto Fedele, Paola Fossa, Olga Bruno
A new series of 3-(cyclopentyloxy)-4-methoxyphenyl derivatives, structurally related to our hit GEBR-4a (1) and GEBR-7b (2), has been designed by changing length and functionality of the chain linking the catecholic moiety to the terminal cycloamine portion. Among the numerous molecules synthesized, compounds 8, 10a, and 10b showed increased potency as PDE4D enzyme inhibitors with respect to 2 and a good selectivity against PDE4A4, PDE4B2, and PDE4C2 enzymes, without both cytotoxic and genotoxic effects. The ability to enhance cAMP level in neuronal cells was assessed for compound 8...
August 28, 2014: Journal of Medicinal Chemistry
Chunyan Chen, Miaomiao Liu, Jing Wu, Xiaolan Yang, Xiaolei Hu, Jun Pu, Gaobo Long, Yanling Xie, Hairong Jiang, Yonghua Yuan, Fei Liao
The feasibility for microplate-based screening of inhibitors of isozymes of cyclic nucleotide phosphodiesterase (PDE) was tested via the coupled action of a phosphatase on adenosine-5'-monophosphate and an improved malachite green assay of phosphate. Human full-length PDE4B2 and truncated mutant (152-528aa) were expressed in Escherichia coli via fusion to SUMO, which after purification through Ni-NTA column exhibited specific activities >0.017 U mg(-1). In the presence of proteins <30 mg L(-1), absorbance for 10 µΜ phosphate was measurable; a PDE isozyme of specific activity over 0...
December 2014: Journal of Enzyme Inhibition and Medicinal Chemistry
Taiji Goto, Akiko Shiina, Takeshi Murata, Masato Tomii, Takanori Yamazaki, Ken-ichi Yoshida, Toshiharu Yoshino, Osamu Suzuki, Yoshitaka Sogawa, Kiyoshi Mizukami, Nana Takagi, Tomomi Yoshitomi, Maki Etori, Hiroshi Tsuchida, Tsuyoshi Mikkaichi, Naoki Nakao, Mizuki Takahashi, Hisashi Takahashi, Shigeki Sasaki
A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B...
February 1, 2014: Bioorganic & Medicinal Chemistry Letters
Ling Huang, Wenjun Shan, Qi Zhou, Jiaxing Xie, Kefang Lai, Xingshu Li
A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50=1.05nM, pEC50=9.0) and potent PDE4B2 inhibitory activities (IC50=0.092μM).
January 1, 2014: Bioorganic & Medicinal Chemistry Letters
Yi Zhang, Xiaolan Yang, Xiaolei Hu, Miaomiao Liu, Chunyan Chen, Yanling Xie, Jun Pu, Jing Wu, Gaobo Long, Fei Liao
A resonant-light-scattering (RLS) method was proposed to quantify phosphate for screening inhibitors of isozymes of cyclic nucleotide phosphodiesterase (PDE). In acidified mixtures of phosphate, papaverine and molybdate, there were aggregates exhibiting micrometre sizes, no absorbance peaks over 360 nm but strong RLS peaks at 392 nm; Mie scattering thus accounted for the RLS signals. When papaverine was added before molybdate to acidified samples of phosphate, RLS signals at 392 nm were stable from 5 to 25 min since the addition of molybdate; after optimization, phosphate from 0...
December 4, 2013: Analytica Chimica Acta
Anqiu Liu, Ling Huang, Zhiren Wang, Zonghua Luo, Fei Mao, Wenjun Shan, Jiaxing Xie, Kefang Lai, Xingshu Li
A novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores of salmeterol and roflumilast or phthalazinone. All the compounds exhibited better β(2)-adrenoceptor agonist activities (pEC(50)=8.47-9.20) than the reference compound salmeterol (pEC(50)=8.3) and good inhibitory activity on PDE4B2 (IC(50)=0.235-1.093 μM).
March 1, 2013: Bioorganic & Medicinal Chemistry Letters
Tamam El-Elimat, Mario Figueroa, Huzefa A Raja, Tyler N Graf, Audrey F Adcock, David J Kroll, Cynthia S Day, Mansukh C Wani, Cedric J Pearce, Nicholas H Oberlies
Three bioactive compounds were isolated from an organic extract of an ascomycete fungus of the order Chaetothyriales (MSX 47445) using bioactivity-directed fractionation as part of a search for anticancer leads from filamentous fungi. Of these, two were benzoquinones [betulinan A (1) and betulinan C (3)], and the third was a terphenyl compound, BTH-II0204-207:A (2). The structures were elucidated using a set of spectroscopic and spectrometric techniques; the structure of the new compound (3) was confirmed via single-crystal X-ray diffraction...
March 22, 2013: Journal of Natural Products
Cristina Sanabra, Emily M Johansson, Guadalupe Mengod
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis exhibiting neuroinflammation, axonal damage and demyelination, further characterized by T- and B-cell responses to myelin oligodendrocyte glycoprotein. Pharmacological manipulation of phosphodiesterases (PDEs) provokes profound anti-inflammatory responses through modulation of cAMP levels. The PDE4B subfamily has been related to the inflammatory immune response in mice and PDE4 inhibition produces amelioration of the clinical signs and delayed onset in the EAE model...
January 2013: Journal of Chemical Neuroanatomy
Anthony A Oliva, Yuan Kang, Concepcion Furones, Ofelia F Alonso, Olga Bruno, W Dalton Dietrich, Coleen M Atkins
Traumatic brain injury (TBI) results in significant inflammation which contributes to the evolving pathology. Previously, we have demonstrated that cyclic AMP (cAMP), a molecule involved in inflammation, is down-regulated after TBI. To determine the mechanism by which cAMP is down-regulated after TBI, we determined whether TBI induces changes in phosphodiesterase (PDE) expression. Adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury (FPI) or sham injury, and the ipsilateral, parietal cortex was analyzed by western blotting...
December 2012: Journal of Neurochemistry
Mousumi Ghosh, Daniela Garcia-Castillo, Vladimir Aguirre, Roozbeh Golshani, Coleen M Atkins, Helen M Bramlett, W Dalton Dietrich, Damien D Pearse
Cyclic AMP suppresses immune cell activation and inflammation. The positive feedback loop of proinflammatory cytokine production and immune activation implies that cytokines may not only be regulated by cyclic AMP but also conversely regulate cyclic AMP. This study examined the effects of tumor necrosis factor (TNF)-α and interleukin (IL)-1β on cyclic AMP-phosphodiesterase (PDE) signaling in microglia in vitro and after spinal cord injury (SCI) or traumatic brain injury (TBI). TNF-α or IL-1β stimulation produced a profound reduction (>90%) of cyclic AMP within EOC2 microglia from 30 min that then recovered after IL-1β but remained suppressed with TNF-α through 24 h...
December 2012: Glia
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