Discovery of novel selective phosphodiesterase­1 inhibitors for the treatment of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is the most common form of acute leukemia in adults. PDE1 (Phosphodiesterase 1) is a subfamily of the PDE super-enzyme families that can hydrolyze the second messengers cAMP and cGMP simultaneously. Previous research has shown that suppressing the gene expression of PDE1 can trigger apoptosis of human leukemia cells. However, no selective PDE1 inhibitors have been used to explore whether PDE1 is a potential target for treating AML. Based on our previously reported PDE9/PDE1 dual inhibitor 11a, a series of novel pyrazolopyrimidinone derivatives were designed in this study. The lead compound 6c showed an IC50 of 7.5 nM against PDE1, excellent selectivity over other PDEs and good metabolic stability. In AML cells, compound 6c significantly inhibited the proliferation and induced apoptosis. Further experiments indicated that the apoptosis induced by 6c was through a mitochondria-dependent pathway by decreasing the ratio of Bcl-2/Bax and increasing the cleavage of caspase-3, 7, 9, and PARP. All these results suggested that PDE1 might be a novel target for AML.

Accelerating and Automating the Free Energy Perturbation Absolute Binding Free Energy Calculation with the RED-E Function.

The accurate prediction of the binding affinities between small molecules and biological macromolecules plays a fundamental role in structure-based drug design, which is still challenging. The free energy perturbation-based absolute binding free energy (FEP-ABFE) approach has shown potential in its reliability. To correctly calculate the energy related to the ligand being restrained by the receptor, additional restraints between the ligand and the receptor are needed. However, determining the restraint parameters for individual ligands empirically is too trivial to be automated, and usually gives rise to numerical instabilities, which set back the applications of FEP-ABFE. To address these issues, we derived the analytical expression for the probability distribution of energy differences, P(ΔU), during the process of restraint addition, which is called the RED-E (restraint energy distribution at equilibrium position) function. Simulations indicated that the RED-E function can accurately describe P(ΔU) when restraints are added at the equilibrium position. Based on the RED-E function, an automatic restraint selection method was proposed to select the best restraint. With this method, there is a high phase-space overlap between the free and restrained states, such that using a 2-λ perturbation can accurately calculate the free energy of the restraint addition, which is a nearly 6 times acceleration compared with current widely used 12-λ perturbation method. The RED-E function gives insight into the non-Gaussian behavior of the sampled P(ΔU) in certain FEP processes in an analytical way. The highly automated and accelerated restraint selection also makes it possible for the large-scale application of FEP-ABFE in real drug discovery practices.

Therapeutic targets and potential agents for the treatment of COVID-19.

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.

Discovery of effective phosphodiesterase 2 inhibitors with antioxidant activities for the treatment of Alzheimer's disease.

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.

Design, Synthesis, and Evaluation of Dihydropyranopyrazole Derivatives as Novel PDE2 Inhibitors for the Treatment of Alzheimer's Disease.

Phosphodiesterase 2 (PDE2) has been regarded as a novel target for the treatment of Alzheimer's disease (AD). In this study, we obtained (R)-LZ77 as a hit compound with moderate PDE2 inhibitory activity (IC50 = 261.3 nM) using a high-throughput virtual screening method based on molecular dynamics. Then, we designed and synthesized 28 dihydropyranopyrazole derivatives as PDE2 inhibitors. Among them, compound (+)-11h was the most potent PDE2 inhibitor, with an IC50 value of 41.5 nM. The molecular docking of PDE2-(+)-11h reveals that the 4-(trifluoromethyl)benzyl)oxyl side chain of the compound enters the H-pocket and forms strong hydrophobic interactions with L770/L809/F862, which improves inhibitory activity. The above results may provide insight for further structural optimization of highly potent PDE2 inhibitors and may lay the foundation for their use in the treatment of AD.

Design, synthesis and evaluation of pyrazolopyrimidinone derivatives as novel PDE9A inhibitors for treatment of Alzheimer's disease.

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.

Satisfaction of family members with inpatient psychiatric care and its correlates: a national survey in China.

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 < 0.001). There was no significant sex difference in total family satisfaction scores. Family members with a lower educational background (elementary school or less) had significantly lower satisfaction. Family members of patients who were diagnosed with schizophrenia were significantly less satisfied with doctor-family communication. In different treatment response subgroups, the marked improvement subgroup had significantly higher total satisfaction scores and subscores. Meanwhile, lower self-payment expenses and a higher number of psychologic treatments offered per day were significantly associated with higher total satisfaction scores and all subscores. Logistic regression showed a higher educational background, more psychologic treatments offered per day, adequacy of professional staffing (higher doctor/bed, nurse/bed and psychologist/bed ratio) were all significantly associated with higher family satisfaction. 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.

Screening, synthesis, crystal structure, and molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as novel AKR1C3 inhibitors.

AKR1C3 is a promising therapeutic target for castration-resistant prostate cancer. Herein, an evaluation of in-house library discovered substituted pyranopyrazole as a novel scaffold for AKR1C3 inhibitors. Preliminary SAR exploration identified its derivative 19d as the most promising compound with an IC50 of 0.160 µM among the 23 synthesized molecules. Crystal structure studies revealed that the binding mode of the pyranopyrazole scaffold is different from the current inhibitors. Hydroxyl, methoxy and nitro group at the C4-phenyl substituent together anchor the inhibitor to the oxyanion site, while the core of the scaffold dramatically enlarges but partially occupies the SP pockets with abundant hydrogen bond interactions. Strikingly, the inhibitor undergoes a conformational change to fit AKR1C3 and its homologous protein AKR1C1. Our results suggested that conformational changes of the receptor and the inhibitor should both be considered during the rational design of selective AKR1C3 inhibitors. Detailed binding features obtained from molecular dynamics simulations helped to finally elucidate the molecular basis of 6-amino-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as AKR1C3 inhibitors, which would facilitate the future rational inhibitor design and structural optimization.

Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.

Discovery of Novel Phosphodiesterase-2A Inhibitors by Structure-Based Virtual Screening, Structural Optimization, and Bioassay.

Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer's disease and pulmonary hypertension. However, most of the current PDE2A inhibitors have moderate selectivity over other PDEs. In the present study, we described the discovery of novel PDE2A inhibitors by structure-based virtual screening combining pharmacophore model screening, molecular docking, molecular dynamics simulations, and bioassay validation. Nine hits out of 30 molecules from the SPECS database (a hit rate of 30%) inhibited PDE2A with affinity less than 50 µM. Optimization of compound AQ-390/10779040 (IC50 = 4.6 µM) from the virtual screening, which holds a novel scaffold of benzo[cd]indol-2(1H)-one among PDE inhibitors, leads to discovery of a new compound LHB-8 with a significant improvement of inhibition (IC50 = 570 nM). The modeling studies demonstrated that LHB-8 formed an extra hydrogen bond with Asp808 and a hydrophobic interaction with Thr768, in addition to the common interactions with Gln859 and Phe862 of PDE2A. The novel scaffolds discovered in the present study can be used for rational design of PDE2A inhibitors with high affinity.

Palladium-Catalyzed Decarboxylative Acylation of N-Nitrosoanilines with α-Oxocarboxylic Acids.

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.

3D-QSAR studies of 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids as AKR1C3 inhibitors: Highlight the importance of molecular docking in conformation generation.

AKR1C3 is a promising drug target for castration-resistant prostate cancer (CRPC). Here, 3D-QSAR analysis were performed on 3-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)benzoic acids to correlate their chemical structures with their observed AKR1C3 inhibitory activity. Three structural alignment methods employing various conformers were used to scrutinize the effect of conformation selection on the predictive accuracy of QSAR models. Using docked conformation, the best CoMFA and CoMSIA models were developed and validated with a training set of 61 molecules and a test set of 7 molecules. Detailed analysis of contour maps provided helpful structural insights to rational design of AKR1C3 inhibitors with enhanced potency.

Oxidative coupling between C(sp²)-H and C(sp³)-H bonds of indoles and cyclic ethers/cycloalkanes.

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.

Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.

Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.

Regioselective direct C-3 arylation of imidazo[1,2-a]pyridines with aryl tosylates and mesylates promoted by palladium-phosphine complexes.

Direct C-3 arylation of imidazo[1,2-a]pyridines with aryl tosylates and mesylates has been accomplished by employing palladium(II) acetate associated with SPhos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl) or L1 (2-(2-(diisopropylphosphino)phenyl)-1-methyl-1H-indole). This catalyst system can be applied to a wide range of aryl sulfonates and shows excellent C-3 regioselectivity of imidazo[1,2-a]pyridine. These results represent the first examples of using tosylate- and mesylate-functionalized arenes as the electrophile partners for this regioselective direct arylation.

Direct intermolecular C-H arylation of unactivated arenes with aryl bromides catalysed by 2-pyridyl carbinol.

Direct intermolecular C-H arylation employing aryl bromide as the arene source has been developed. This process proceeds via a simple transition-metal-free pathway. With the aid of inexpensive and commercially available 2-pyridyl carbinol and potassium tert-butoxide, various unactivated arene C-H bonds can be directly arylated by aryl bromides through homolytic aromatic substitution.

The therapeutic potential of phosphodiesterase 9 (PDE9) inhibitors: a patent review (2018-present).

INTRODUCTION: Phosphodiesterase 9 (PDE9) has been demonstrated as a potential target for neurological disorders and cardiovascular diseases, such as Alzheimer's disease and heart failure. For the last few years, a series of PDE9 inhibitors with structural diversities have been developed and patented by researchers and pharmaceutical companies, providing insights into first-in-class therapies of PDE9 drug candidates. AREA COVERED: This review provides an overview of PDE9 inhibitors in patents from 2018 to the present. EXPERT OPINION: Only a few of the current PDE9 inhibitors are highly selective over other PDEs, which limits their application in pharmacological and clinical research. The design and development of highly selective PDE9 inhibitors remain the top priority in future research. The advantages of targeting PDE9 rather than other PDEs in treating neurodegenerative diseases need to be explained thoroughly. Besides, application of PDE9 inhibitor-based combination therapies sheds light on treating diabetes and refractory heart diseases. Finally, PDE9 inhibitors should be further explored in clinical indications beyond neurological disorders and cardiovascular diseases.

Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis.

Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-ß-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

AtMYB72 aggravates photosynthetic inhibition and oxidative damage in Arabidopsis thaliana leaves caused by salt stress.

MYB transcription factor is one of the largest families in plants. There are more and more studies on plants responding to abiotic stress through MYB transcription factors, but the mechanism of some family members responding to salt stress is unclear. In this study, physiological and transcriptome techniques were used to analyze the effects of the R2R3-MYB transcription factor AtMYB72 on the growth and development, physiological function, and key gene response of Arabidopsis thaliana. Phenotypic observation showed that the damage of overexpression strain was more serious than that of Col-0 after salt treatment, while the mutant strain showed less salt injury symptoms. Under salt stress, the decrease of chlorophyll content, the degree of photoinhibition of photosystem II (PSII) and photosystem I (PSI) and the degree of oxidative damage of overexpressed lines were significantly higher than those of Col-0. Transcriptome data showed that the number of differentially expressed genes (DEGs) induced by salt stress in overexpressed lines was significantly higher than that in Col-0. GO enrichment analysis showed that the response of AtMYB72 to salt stress was mainly by affecting gene expression in cell wall ectoplast, photosystem I and photosystem II, and other biological processes related to photosynthesis. Compared with Col-0, the overexpression of AtMYB72 under salt stress further inhibited the synthesis of chlorophyll a (Chla) and down-regulated most of the genes related to photosynthesis, which made the photosynthetic system more sensitive to salt stress. AtMYB72 also caused the outbreak of reactive oxygen species and the accumulation of malondialdehyde under salt stress, which decreased the activity and gene expression of key enzymes in SOD, POD, and AsA-GSH cycle, thus destroying the ability of antioxidant system to maintain redox balance. AtMYB72 negatively regulates the accumulation of osmotic regulatory substances such as soluble sugar (SS) and soluble protein (SP) in A. thaliana leaves under salt stress, which enhances the sensitivity of Arabidopsis leaves to salt. To sum up, MYB72 negatively regulates the salt tolerance of A. thaliana by destroying the light energy capture, electron transport, and antioxidant capacity of Arabidopsis.

A radical process towards the development of transition-metal-free aromatic carbon-carbon bond-forming reactions.

Transition-metal-free cross-coupling reactions have been a hot topic in recent years. With the aid of a radical initiator, a number of unactivated arene C-H bonds can be directly arylated/functionalized by using aryl halides through homolytic aromatic substitution. Commercially available or specially designed promoters (e.g. diamines, diols, and amino alcohols) have been used to make this synthetically attractive method viable. This protocol offers an inexpensive, yet efficient route to aromatic C-C bond formations since transition metal catalysts and impurities can be avoided by using this reaction system. In this article, we focus on the significance of the reaction conditions (e.g. bases and promoters), which allow this type of reaction to proceed smoothly. Substrate scope limitations and challenges, as well as mechanistic discussion are also included.