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PDE1 has been demonstrated to be a potential drug target for a variety of diseases, such as Alzheimer's disease and cardiovascular disease. In the past decades, numerous PDE1 inhibitors with structural diversities have been developed and patented by pharmaceutical companies, providing drug candidates for exploring novel disease indications of PDE1.This review aims to provide an overview of PDE1 inhibitors reported in patents from 2008 to present.Among current PDE1 inhibitors, only a few of them showed high selectivity over other PDEs, which might cause severe side effects in the clinic. The development of highly selective PDE1 inhibitors is still the 'top priority' in the following research. The selective recognition mechanism of PDE1 with inhibitors should be further elucidated by X-ray crystallography in order to provide evidence for the rational design of selective PDE1 inhibitors. In addition, PDE1 inhibitors should be applied to different clinical indications beyond CNS diseases.

Background Circular RNAs (CircRNAs) have been found to possess vital functions in tumorigenesis of various cancer types, including non-small cell lung cancer (NSCLC). The aim of this study was to identify and explore the diagnostic values of the newly found Toll interacting protein (TOLLIP)-derived circRNA (circTOLLIP) for liquid biopsy in NSCLC. Methods RNase R and actinomycin D assays were conducted to confirm the existence and stability of circTOLLIP. RT-qPCR was performed to identify the expression levels of circTOLLIP in NSCLC tumor tissues, whole blood, and cell lines. The diagnostic values were evaluated by receiver operating characteristic (ROC) curve analysis. Results CircTOLLIP was screened as a candidate biomarker and was found to be significantly down-regulated in both NSCLC tissues and cell lines. Interestingly, circulating circTOLLIP was also lower-expressed in the whole blood of patients with NSCLC compared to that of patients with benign lung disease and healthy controls. Importantly, the circulating circTOLLIP represented better diagnostic values in comparison to the traditional tumor markers (NSE, CYFR21-1, and CA72-4), and showed higher stability even though the whole blood was exposed to various tough conditions. Conclusions Our findings indicate that circTOLLIP can be used as a non-invasive biomarker to distinguish early-stage NSCLC from benign lung diseases and from healthy controls, suggesting the potential application of circTOLLIP for liquid biopsy in NSCLC.

Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound

To validate the hypothesis that Tyr748 is a crucial residue to aid the discovery of highly selective phosphodiesterase 8A (PDE8A) inhibitors, we identified a series of 2-chloroadenine derivatives based on the hit clofarabine. Structure-based design targeting Tyr748 in PDE8 resulted in the lead compound 3a (IC50 = 0.010 μM) with high selectivity with a reasonable druglike profile. In the X-ray crystal structure, 3a bound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 A with Tyr748, which possibly interprets the 220-fold selectivity of 3a against PDE2A. Additionally, oral administration of compound 3a achieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.

Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor A. As a result, a potent and highly selective PDE10A inhibitor, 14·3HCl (half maximal inhibitory concentration, IC50 = 2.8 nmol/L and >3500-fold selectivity) exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of 50% was identified with the aid of efficient methods of binding free energy predictions. Animal PAH studies showed that the improvement offered by 14·3HCl [2.5 mg/kg, oral administration (p.o.)] was comparable to tadalafil (5.0 mg/kg, p.o.), verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment. The crystal structure of the PDE10A−14 complex illustrates their binding pattern, which provided a guideline for rational design of highly selective PDE10A inhibitors., Graphical abstract A potent and highly selective PDE10A inhibitor, 14·3HCl (IC50 = 2.8 nmol/L and >3500-folds selectivity) with a remarkable bioavailability of 50% was obtained to verify the feasibility for the anti-PAH treatment. The crystal structure of PDE10A–14 complex illustrated the binding pattern, providing a guideline for rational design of highly selective PDE10A inhibitors.Image 1

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe

Hepatic fibrosis commonly exists in chronic liver disease and would eventually develop to cirrhosis and liver cancer with high fatality. Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug target because of its highest binding affinity among phosphodiesterases (PDEs) with cyclic guanosine monophosphate. However, no published study has reported PDE9 inhibitors as potential agents against hepatic fibrosis yet. Herein, structural modification from a starting hit LL01 led to lead 4a, which exhibited an IC50 value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with 4a revealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of 4a exerted a significant antifibrotic effect in bile duct-ligation-induced rats with hepatic fibrosis and transforming growth factor-β-induced fibrogenesis. This therapeutic effect was indeed achieved by selectively inhibiting PDE9 rather than other PDE isoforms, identifying PDE9 inhibitors as potential agents against hepatic fibrosis.

Dan Liu,1 Yinuo Wu,2 Feng Jiang,3 Yuanli Liu,1 Yi-Lang Tang4,5 1School of Health Policy and Management, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 3Hospital Management and Evaluation Research Center, Institute of Healthy Yangtze River Delta, Shanghai Jiao Tong University, Shanghai, People’s Republic of China; 4Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA; 5Atlanta VA Medical Center, Atlanta, GA, USACorrespondence: Yuanli LiuSchool of Health Policy and Management, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 3 Dong Dan San Tiao, Dongcheng District, Beijing, People’s Republic of ChinaEmail liuyl_fpo@126.comBackground: Sleep is an essential component of health and well-being. Short sleep duration may negatively affect nurses’ health and patients’ safety.Objective: To investigate the sleep duration and subjective satisfaction with sleep duration among nurses in tertiary public hospitals in China and to explore the associated factors.Methods: This cross-sectional study was conducted between December 18 and 31, 2017 in 136 major public hospitals from 31 provinces in mainland China. An online anonymous questionnaire was delivered through WeChat. Totally 27,575 nurses completed the survey.Results: The response rate was 95.46%. The mean reported total sleep duration was 6.67± 0.97 hours per day. About 46.87% (n=12,924) reported having short sleep duration (SSD, less than 7 hours per day), and 27.63% (n=7618) were not satisfied with their sleep duration. In the SSD group, 45.67% (n=5902) were dissatisfied with their sleep duration. SSD was significantly associated with sociodemographic factors, including an older age, having more than one child, being divorced or separated, and job-related factors, including longer working hours, more night shifts and heavy workload.Conclusion: Nearly half of the nurses in the public hospitals in China reported sleeping less than 7 hours, and more than one quarter were dissatisfied with their sleep duration. Interventions are needed to improve Chinese nurses’ sleep, including reducing working hours, night shifts or workload.Keywords: short sleep duration, prevalence, satisfaction, nurse, tertiary public hospitals

A challenge for sensors targeting specific enzymes of interest in their native environment for direct imaging is that they rationally exploit a highly selective fluorescent probe with a high binding affinity to provide real-time detection. Immunohistochemical staining, proteomic analysis, or recent enzymatic fluorescent probes are not optimal for tracking specific enzymes directly in living cells. Herein, we introduce the concept of designing a highly effective fluorescent probe (BVQ1814) targeting phosphodiesterase 10A with a highly potent affinity and a >1000-fold subfamily selectivity by gaining insights into the three-dimensional structural information of the active site of the catalytic pocket. BVQ1814 showed an outstanding binding affinity for PDE10A in vitro and specifically detected PDE10A in living cells, indicating that most PDE10A was probably distributed in the lysosomes. We validated the PDE10A distribution in stable mCherry-PDE10A-overexpressing HepG2 cells. This probe delineated the profile of PDE10A in tissue sections and exhibited a remarkable therapeutic effect as a PDE10A inhibitor for treating pulmonary arterial hypertension. This concept will open up a new avenue for designing a highly effective fluorescent probe for tracking receptor proteins by taking full advantage of the structural information in the ligand-binding pocket of the target of interest.

The outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global crisis. As of November 9, COVID-19 has already spread to more than 190 countries with 50,000,000 infections and 1,250,000 deaths. Effective therapeutics and drugs are in high demand. The structure of SARS-CoV-2 is highly conserved with those of SARS-CoV and Middle East respiratory syndrome-CoV. Enzymes, including RdRp, Mpro /3CLpro , and PLpro , which play important roles in viral transcription and replication, have been regarded as key targets for therapies against coronaviruses, including SARS-CoV-2. The identification of readily available drugs for repositioning in COVID-19 therapy is a relatively rapid approach for clinical treatment, and a series of approved or candidate drugs have been proven to be efficient against COVID-19 in preclinical or clinical studies. This review summarizes recent progress in the development of drugs against SARS-CoV-2 and the targets involved.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease lacking effective therapy. To identify whether phosphodiesterase-1 (PDE1) inhibition could act as a novel target for the treatment of IPF, hit-to-lead structural optimizations were performed on the PDE9/PDE1 dual inhibitor (R)-C33, leading to compound 3m with an IC50 of 2.9 nM against PDE1C, excellent selectivity across PDE subfamilies, reasonable drug-like properties, and remarkable pharmacodynamic effects as an anti-IPF agent. Oral administration of compound 3m (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model and prevented transforming growth factor-β-induced fibroblast-to-myofibroblast conversion in vitro, indicating that PDE1 inhibition could serve as a novel target for the efficient treatment of IPF.

Phosphodiesterase-9 (PDE9) is a promising target for the treatment of Alzheimer’s disease (AD). To discover efficient PDE9 inhibitors with good metabolic stability and solubility, a series of novel pyrazolopyrimidinone derivatives have been designed with the assistance of molecular docking and dynamics simulations. All the fourteen synthesized compounds gave excellent inhibition ratio against PDE9 at 10 nM. Compound 1k with the IC50 of 2.0 nM against PDE9, showed good metabolic stability (t1/2 of 57 min) in the RLM as well as good solubility (195 mg/L). The analysis on binding modes of targeted compounds may provide insight for further structural modification.

Alzheimer’s disease (AD) is one of the greatest public health challenges. Phosphodiesterases (PDEs) are a superenzyme 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 15 of them have been subjected to clinical trials. The aim of this review is to summarize the outstanding progress that has been made by PDE inhibitors as anti-AD agents with encouraging results in preclinical studies and clinical trials. The binding affinity, pharmacokinetics, underlying mechanisms, and limitations of these PDE inhibitors in the treatment of AD are also rev...

A method for the transition-metal-free direct C–H arylation of unactivated arenes is developed with aryl bromides as substrates and 8-hydroxyquinoline as an efficient promoter. A variety of biaryl compounds with structural diversity are obtained in moderate to high yields. Mechanistic studies reveal that the reaction proceeds via a homolytic­ aromatic substitution pathway.

Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer’s disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone–rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC50 values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC50, 6c, 3.3 μM; 6f, 0.97 μM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy m...

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.

Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington's disease. Recently, a hit compound

Background Measuring family members’ satisfaction with inpatient psychiatric care may help improve the quality of healthcare in psychiatric hospitals. This survey aimed to investigate the satisfaction of family members with inpatient psychiatric care and to explore its associated factors, using a newly-developed 5-item questionnaire. Methods This study included 1598 family members of psychiatric inpatients in 32 tertiary public psychiatric hospitals in 29 provinces of China. Satisfaction and demographic data were collected by research staff while patient and hospital data were retrieved separately. Results We found that the overall satisfaction level was 93.84% (23.46/25). The total satisfaction score in Northeast China was the highest, followed by the East, Middle and West regions (p Conclusions We suggest government and hospital managers recruit more mental health professions to improve family satisfaction. If feasible, providing more psychologic treatments to inpatients may also improve families’ satisfaction and involvement.

Background N-terminal pro-B-type natriuretic peptide (NT-proBNP) may provide incremental prognostic value in valvular heart disease (VHD). We aimed to elaborate its value in elder VHD patients and relationship with ventricular function and prognosis. Methods From China elDerly Valvular heart Disease (China-DVD) cohort study, elder VHD patients (age ≥60 years) with concomitant echocardiography and NT-proBNP measurements at baseline were included. Patients were followed every six months. The primary endpoint was 1-year all-cause mortality regardless of valvular intervention. Results In total, 6025 patients were included in the study (mean age of 71.08±7.61 years, 52.6% male, 78.6% NYHA class > I). The overall median NT-proBNP was 268.92 pmol/L (interquartile range [IQR]: 89.94 to 828.70 pmol/L). Among various VHD, the highest NT-proBNP levels were detected in patients with multivalvular heart disease (379.96 pmol/L [IQR: 146.07 to 1188.53 pmol/L]) and mitral regurgitation (294.88 pmol/L [IQR: 98.44 to 917.75 pmol/L), and the lowest levels were observed in patients with aortic regurgitation (112.04 pmol/L [IQR: 31.92 to 408.04 pmol/L). NT-pro BNP levels correlated with age (r=0.131, p Conclusion Levels of NT-proBNP significantly differ by diagnosis in VHD patients and correlate with echocardiographic parameters to varying degrees, reflecting different hemodynamic changes. In patients with VHD other than single mitral stenosis, NT-proBNP is a powerful, independent, and incremental predictor of mortality. Thus, measurement of NT-proBNP should be considered in the VHD population for further risk stratification. Acknowledgement/Funding Key Projects in the National Science & Technology Pillar Program during the 12th five-year Plan

Background Coronary artery ectasia (CAE) bears high risk of death and myocardial infarction. Risk stratification in CAE patients is crucial for their management, but there were no risk score systems intended for risk evaluation of CAE patients so far. Methods In a retrospective cohort of 595 patients with CAE, we collected the baseline characteristics (clinical history, biomarkers and quantitative coronary angiography variables). Follow-up were conducted and the end-point event was the composite of all-cause death and non-fatal myocardial infarction. The candidate predictors of end-point event were analyzed using Cox proportional hazards regression models to derive a risk score in the form of nomogram. The predictive performance and discriminative ability of the novel nomogram were determined by concordance index (C-index) and calibration curve, that were validated internally. Risk stratification by nomogram-predicted risk score was further evaluated. Results During a median follow-up time of 62.3 months, 26 all-cause deaths and 37 non-fatal myocardial infarctions were identified. The final risk-prediction model named ABCD-CAE score included four items: age (A), Brain natriuretic peptide (B), high sensitivity C-reactive protein (C) and maximum Dilated area of ectatic lesions (D). The nomogram yielded a C-index for end-point event of 0.72 (95% confidence interval, 0.64 - 0.79). The calibration curve demonstrated that there is good agreement between prediction by nomogram and actual observation of end-point events. Compared with the low-risk group (score ≤100), the risk of composite events was significantly increased in the intermediate-risk group (score: 100–130) and high-risk group (score >130) [hazard ratio (95% confidence interval): 2.23 (1.23–4.06), P=0.008 and 7.02 (3.81–12.97), P ABCD-CAE nomogram for risk prediction Conclusions The ABCD-CAE score is a simple four-item risk score, that provides a clinically useful tool for the risk prediction of all-cause death and myocardial infarction in patients with CAE. This user-friendly tool might support clinical decision making for the management of CAE.

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.

The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer’s disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC50 of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure–activity relationship (SAR) of lead compounds.

Accurate prediction of absolute protein-ligand binding free energy could considerably enhance the success rate of structure-based drug design but is extremely challenging and time-consuming. Free energy perturbation (FEP) has been proven reliable but is limited to prediction of relative binding free energies of similar ligands (with only minor structural differences) in binding with a same drug target in practical drug design applications. Herein, a Gaussian algorithm-enhanced FEP (GA-FEP) protocol has been developed to enhance the FEP simulation performance, enabling to efficiently carry out the FEP simulations on vanishing the whole ligand and, thus, predict the absolute binding free energies (ABFEs). Using the GA-FEP protocol, the FEP simulations for the ABFE calculation (denoted as GA-FEP/ABFE) can achieve a satisfactory accuracy for both structurally similar and diverse ligands in a dataset of more than 100 receptor-ligand systems. Further, our GA-FEP/ABFE-guided lead optimization against phosphodiesterase-10 led to the discovery of a subnanomolar inhibitor (IC

Phosphodiesterase 10 is a promising target for the treatment of a series of central nervous system (CNS) diseases. Imbalance between oxidative stress and antioxidant defense systems as a universal condition in neurodegenerative disorders is widely studied as a potential therapy for CNS diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). To discover multifunctional pharmaceuticals as a treatment for neurodegenerative diseases, a series of quinazoline-based derivatives with PDE10 inhibitory activities and antioxidant activities were designed and synthesized. Nine out of 13 designed compounds showed good PDE10 inhibition at the concentration of 1.0 μM. Among these compounds, eight exhibited moderate to excellent antioxidant activity with ORAC (oxygen radical absorbance capacity) value above 1.0. Molecular docking was performed for better understanding of the binding patterns of these compounds with PDE10. Compound 11e, which showed remarkable inhibitory activity against PDE10 and antioxidant activity may serve as a lead for the further modification.

A palladium-catalyzed oxidative C-H bond decarboxylative acylation of N-nitrosoanilines using α-oxocarboxylic acid as the acyl source is described. The catalyst Pd(OAc)2 and oxidant (NH4)2S2O8 enabled ortho-acylation of N-nitrosoanilines at room temperature, affording an array of N-nitroso-2-aminobenzophenones in moderate to excellent yields.

Cross-dehydrogenative-coupling (CDC) between C–H/C–H bonds of indoles and cyclic ethers/cycloalkanes is made viable through a simple transition-metal-free pathway. With the aid of only di-tert-butyl peroxide, a number of inactive cyclic ethers and cycloalkanes can be directly coupled with indole derivatives in satisfactory yields.

Phosphodiesterase 9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of diabetes and Alzheimer’s disease. Here we report a potent PDE9 inhibitor 3r that has an IC50 of 0.6 nM and >150-fold selectivity over other PDEs. The HepG2 cell-based assay shows that 3r inhibits the mRNA expression of phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. These activities of 3r, together with the reasonable pharmacokinetic properties and no acute toxicity at 1200 mg/kg dosage, suggest its potential as a hypoglycemic agent. The crystal structure of PDE9-3r reveals significantly different conformation and hydrogen bonding pattern of 3r from those of previously published 28s. Both 3r and 28s form a hydrogen bond with Tyr424, a unique PDE9 residue (except for PDE8), but 3r shows an additional hydrogen bond with Ala452. This structure information might be useful for design of PDE9 inhibitors.