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PDE inhibitor.

Shawn J Stachel, Melissa S Egbertson, Jenny Wai, Michelle Machacek, Dawn M Toolan, John Swestock, Donnie M Eddins, Vanita Puri, Georgia McGaughey, Hua-Poo Su, Debbie Perlow, Deping Wang, Lei Ma, Gopal Parthasarathy, John C Reid, Pravien D Abeywickrema, Sean M Smith, Jason M Uslaner
An internal HTS effort identified a novel PDE2 inhibitor series that was subsequently optimized for improved PDE2 activity and off-target selectivity. The optimized lead, compound 4, improved cognitive performance in a rodent novel object recognition task as well as a non-human primate object retrieval task. In addition, co-crystallization studies of close analog of 4 in the PDE2 active site revealed unique binding interactions influencing the high PDE isoform selectivity.
April 1, 2018: Bioorganic & Medicinal Chemistry Letters
Teemu T Turunen, Ari Koskelainen
Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cAMP and cGMP. PDEs control numerous cellular processes making them promising targets for the development of therapeutic agents. Unfortunately, many PDE inhibitor molecules are non-selective among PDE classes and efficient methods for quantitative studies on the isoform-specificity of PDE inhibitors in the natural environments of PDEs are unavailable. The PDE in photoreceptors, PDE6, mediates the conversion of photon information into electrical signals making the retina an exceptional model system for examinations of the pharmacological effects of PDE inhibitors on PDE6...
March 5, 2018: Toxicology and Applied Pharmacology
Andreas Krause, Jochen Zisowsky, Jasper Dingemanse
BACKGROUND: Macitentan is the first endothelin receptor antagonist with demonstrated efficacy on morbidity and mortality in pulmonary arterial hypertension (PAH) in the pivotal study SERAPHIN. METHODS: The pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, were characterized in a population model. Efficacy and hemodynamics (pharmacodynamics, PD) were related to PK based on PK/PD modeling. RESULTS: Sex, age, and body weight influenced the PK to a statistically significant extent...
February 28, 2018: Pulmonary Pharmacology & Therapeutics
Yoichi Kadoh, Haruko Miyoshi, Takehiko Matsumura, Yoshihito Tanaka, Mitsuya Hongu, Mayumi Kimura, Kei Takedomi, Kenji Omori, Jun Kotera, Takashi Sasaki, Tamaki Kobayashi, Hiroyuki Taniguchi, Yumi Watanabe, Koki Kojima, Toshiaki Sakamoto, Toshiyuki Himiyama, Eiji Kawanishi
Phosphodiesterase (PDE) 10A is a dual hydrolase of cAMP and cGMP and highly expressed in striatal medium spiny neurons. Inhibition of PDE10A modulates the activity of medium spiny neurons (MSN) via the regulation of cAMP and cGMP. Signal control of MSN is considered associated with psychotic symptoms. Therefore PDE10A inhibitor is expected as a therapeutic method for psychosis disease such as schizophrenia. Avanafil (1) is a PDE5 inhibitor (treatment for erectile dysfunction) discovered by our company. We paid attention to the homology of PDE10A and PDE5 and took advantage of PDE5 inhibitor library to discover PDE10A inhibitors, and found a series of compounds that exhibit higher potency for PDE10A than PDE5...
2018: Chemical & Pharmaceutical Bulletin
Ateş Kadıoğlu, Emre Salabaş, Abdulkadir Özmez, Abdullah Feyyaz Ural, Ömer Barış Yücel, Mazhar Ortaç, Yaşar Pazır, Bahadır Ermeç
Objective: To assess the outcomes of the surgical techniques used in Peyronie's disease (PD) surgery. Material and methods: Two hundred and sixty-eight patients received surgical treatment for PD. Fifty four and 144 patients underwent simple corporoplasties (shortening procedure, SP, group 1) or plaque incision and grafting surgery (lengthening surgery, LP, group 2), respectively, whereas 70 patients with erectile dysfunction underwent penile prosthesis implantation...
January 2018: Turkish Journal of Urology
Bahia A Moussa, Asmaa A El-Zaher, Mohamed K El-Ashrey, Marwa A Fouad
In the present work, we designed and synthesized new roflumilast analogues with preferential-selective PDE-4B inhibition activity and improved pharmacokinetic properties. The unsubstituted benzo[d]thiazol-2-yl and -6-yl benzamide derivatives (4a and 6a) showed both good potency and preferential selectivity for PDE-4B. More remarkably, 6c revealed 6 times preferential PDE-4B/4D selectivity with a significant increase of in vitro cAMP and good % inhibition of TNF-α concentration. In addition, the in vitro pharmacokinetics of 6c showed good metabolic stability with in vitro CLint (5...
February 17, 2018: European Journal of Medicinal Chemistry
Prabhjot Singh, Shilpa Vijayakumar, Andreas Kalogeroupoulos, Javed Butler
PURPOSE OF REVIEW: This review discusses the integral role of the nitric oxide (NO) pathway in the pathophysiology of heart failure (HF). We emphasize potential therapeutic targets in the NO pathway and review contemporary clinical trials evaluating these novel therapeutic options. RECENT FINDINGS: Nitrates, neprilysin inhibitors, and phosphodiesterase (PDE) inhibitors have all proven to be efficacious in HF patients with systolic dysfunction, with the former two classes of medications producing a net mortality benefit...
February 24, 2018: Current Heart Failure Reports
Fernando Bartolome, Macarena de la Cueva, Consuelo Pascual, Desiree Antequera, Tamara Fernandez, Carmen Gil, Ana Martinez, Eva Carro
BACKGROUND: The phosphodiesterase (PDE) 7 inhibitor S14 is a cell-permeable small heterocyclic molecule that is able to cross the blood-brain barrier. We previously found that intraperitoneal treatment with S14 exerted neuroprotection in an Alzheimer's disease (AD) model (in APP/PS1 mice). The objective of this study was to investigate the neurogenic and cellular effects of oral administration of S14 on amyloid β (Aβ) overload. METHODS: We orally administered the PDE7 inhibitor S14 (15 mg/kg/day) or vehicle in 6-month-old APP/PS1 mice...
February 20, 2018: Alzheimer's Research & Therapy
P R A Heckman, A Blokland, E P P Bollen, J Prickaerts
The corticostriatal and hippocampal circuits contribute to the neurobiological underpinnings of several neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease and schizophrenia. Based on biological function, these circuits can be clustered into motor circuits, associative/cognitive circuits and limbic circuits. Together, dysfunctions in these circuits produce the wide range of symptoms observed in related neuropsychiatric disorders. Intracellular signaling in these circuits is largely mediated through the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway with an additional role for the cyclic guanosine monophosphate (cGMP)/ protein kinase G (PKG) pathway, both of which can be regulated by phosphodiesterase inhibitors (PDE inhibitors)...
February 15, 2018: Neuroscience and Biobehavioral Reviews
Charles D Burger, A Burak Ozbay, Howard M Lazarus, Ellen Riehle, Leslie B Montejano, Gregory Lenhart, R James White
BACKGROUND: Despite multiple treatment options, the prognosis of pulmonary arterial hypertension (PAH) remains poor. PAH patients experience a high economic burden due to comorbidities, hospitalizations, and medication costs. Although combination therapy has been shown to reduce hospitalizations, the relationship between treatment, health care utilization, and costs remains unclear. OBJECTIVE: To provide a characterization of health care utilization and costs in real-world settings by comparing periods before and after initiating PAH-specific treatment...
February 13, 2018: Journal of Managed Care & Specialty Pharmacy
Grażyna Chłoń-Rzepa, Agnieszka Jankowska, Marietta Ślusarczyk, Artur Świerczek, Krzysztof Pociecha, Elżbieta Wyska, Adam Bucki, Alicja Gawalska, Marcin Kołaczkowski, Maciej Pawłowski
A novel butanehydrazide derivatives of purine-2,6-dione designed using a ligand-based approach were synthesized and their in vitro activity against both PDE4B and PDE7A isoenzymes was assessed. The 7,8-disubstituted purine-2,6-dione derivatives 31, 34, 37, and 40 appeared to be the most potent PDE4/7 inhibitors with IC50 values in the range of that of the reference rolipram and BRL-50481, respectively. Moreover, docking studies explained the importance of N-(2,3,4-trihydroxybenzylidene)butanehydrazide substituent in position 7 of purine-2,6-dione core for dual PDE4/7 inhibitory properties...
January 27, 2018: European Journal of Medicinal Chemistry
Lu-Fei Shen, Xiao-Dong Lv, Wen-Yu Chen, Qi Yang, Zhi-Xian Fang, Wei-Fen Lu
BACKGROUND: Randomized controlled trials (RCTs) of roflumilast effect on chronic obstructive pulmonary disease (COPD) have been reported in the last decade. The current meta-analysis was designed to systematically review and perform meta-analysis of the RCTs of roflumilast treatment in COPD. METHODS: Electronic databases including PubMed, EMBASE, Web of Science, and Cochrane clinical trials database were searched to identify RCTs of roflumilast treatment on COPD...
February 3, 2018: Irish Journal of Medical Science
Peter Deibert, Adhara Lazaro, Zoran Stankovic, Denise Schaffner, Martin Rössle, Wolfgang Kreisel
Non-selective beta-blockers are the mainstay of medical therapy for portal hypertension in liver cirrhosis. Inhibitors of phosphodiesterase-5 (PDE-5-inhibitors) reduce portal pressure in the acute setting by > 10% which may suggest a long-term beneficial effect. Currently, there is no available data on long-term treatment of portal hypertension with PDE-5-inhibitors. This case of a patient with liver cirrhosis secondary to autoimmune liver disease with episodes of bleeding from esophageal varices is the first documented case in which a treatment with a PDE-5-inhibitor for eight years was monitored...
January 21, 2018: World Journal of Gastroenterology: WJG
Bracy A Fertig, George S Baillie
cAMP is the archetypal and ubiquitous second messenger utilised for the fine control of many cardiovascular cell signalling systems. The ability of cAMP to elicit cell surface receptor-specific responses relies on its compartmentalisation by cAMP hydrolysing enzymes known as phosphodiesterases. One family of these enzymes, PDE4, is particularly important in the cardiovascular system, where it has been extensively studied and shown to orchestrate complex, localised signalling that underpins many crucial functions of the heart...
January 31, 2018: Journal of Cardiovascular Development and Disease
Sara Safaripour, Yasaman Nemati, Siavash Parvardeh, Shiva Ghafghazi, Anahita Fouladzadeh, Mahsa Moghimi
OBJECTIVES: The main purpose of this study was to assess the role of l-arginine/SNAP/NO/cGMP/KATP channel pathway in analgesic effects of α-terpineol in mice. METHODS: Male NMRI mice were pretreated intraperitoneally with NO precursor (l-arginine, 100 mg/kg), NO synthase inhibitor (l-NAME, 30 mg/kg), NO donor (SNAP, 1 mg/kg), guanylyl cyclase inhibitor (methylene blue, 20 mg/kg), PDE inhibitor (sildenafil, 0.5 mg/kg), KATP channel blocker (glibenclamide, 10 mg/kg) and naloxone (2 mg/kg) 20 min before the administration of α-terpineol...
January 30, 2018: Journal of Pharmacy and Pharmacology
A A Kamalov, A M Takhirzade
The article reviews the results of various conservative treatments for concomitant benign prostatic hyperplasia (BPH) and erectile dysfunction (ED). Phosphodiesterase type 5 (PDE5) inhibitors remain the first-line therapy for this category of patients taking into account their positive effect on both ED and BPH. The preferred treatment scheme includes PDE-5 inhibitor co-administered with 1-adrenoblocker. However, other combination treatments are considered promising, for example, a PDE-5 inhibitor with a 5-reductase inhibitor or a three-component treatment regimen: 1-adrenoblocker + 5-reductase inhibitor + PDE-5 inhibitor...
December 2017: Urologii︠a︡
J Mokry, A Urbanova, I Medvedova, M Kertys, P Mikolka, P Kosutova, D Mokra
Selective phosphodiesterase (PDE) 4 inhibitors have recently been introduced into the therapy of chronic obstructive pulmonary disease. However, suppression of airway reactivity and eosinophilic inflammation by increased intracellular cAMP could be beneficial in bronchial asthma as well. PDE5 inhibitors are used for the therapy of erectile dysfunction, pulmonary hypertension, and other cardiovascular diseases, but an expression of PDE5 in several immune cells suggests its perspectives in inflammation, as well...
October 2017: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Yinuo Wu, Zhe Li, Yiyou Huang, Deyan Wu, Hai-Bin Luo
Alzheimer's disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs) are a super enzyme family responsible for the hydrolysis of two second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Since several PDE subfamilies are highly expressed in the human brain, the inhibition of PDEs is involved in neurodegenerative processes by regulating the concentration of cAMP and/or cGMP. Currently, PDEs are considered as promising targets for the treatment of AD since many PDE inhibitors have exhibited remarkable cognitive improvement effects in preclinical studies and over fifteen of them have been subjected to clinical trials...
January 24, 2018: Journal of Medicinal Chemistry
Carlos Alberto Arcaro, Renata Pires Assis, Neusa Maria Zanon, Sílvia Paula-Gomes, Luiz C C Navegantes, Isis Carmo Kettelhut, Iguatemy Lourenço Brunetti, Amanda Martins Baviera
Advances in the knowledge of the mechanisms controlling protein breakdown in skeletal muscles have allowed the exploration of new options for treating muscle wasting conditions. Pentoxifylline (PTX), a nonselective phosphodiesterase (PDE) inhibitor, attenuates the loss of muscle mass during catabolic conditions, mainly via inhibiting protein breakdown. The aim of this study was to explore the mechanisms by which PTX inhibits proteolysis in the soleus and extensor digitorum longus (EDL) muscles of streptozotocin-induced diabetic rats...
December 14, 2017: Journal of Applied Physiology
Baskaran Purushothaman, Parthasarathy Arumugam, Goutam Kulsi, Joon Myong Song
Selective inhibition of phosphodiesterase (PDE) 4B favorably suppresses the synthesis of inflammatory cytokines and subsequently arrest the development of atopic dermatitis via modulating the intracellular cAMP levels. Considering the side effects of corticosteroids, selective PDE4 inhibition could constitute an effective alternative therapy for the treatment of atopic dermatitis (AD). In this study, a series of novel catechol based compounds bearing pyrimidine as the core have been synthesized and screened for the PDE4 inhibitory properties...
December 19, 2017: European Journal of Medicinal Chemistry
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