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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 IC 50 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-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.

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 IC 50 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.

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.

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 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC 50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC 50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t 1/2 = 105 min) by using an integrated strategy (molecular modeling, chemical synthesis, bioassay, and cocrystal structure). The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, respectively, thereby resulting in high selectivity against other PDEs. These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.

Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.

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 reviewed and discussed.

Scaffold hopping refers to computer-aided screening for active compounds with different structures against the same receptor to enrich privileged scaffolds, which is a topic of high interest in organic and medicinal chemistry. However, most approaches cannot efficiently predict the potency level of candidates after scaffold hopping. Herein, we identified potent PDE5 inhibitors with a novel scaffold via a free energy perturbation (FEP)-guided scaffold-hopping strategy, and FEP shows great advantages to precisely predict the theoretical binding potencies Δ G FEP between ligands and their target, which were more consistent with the experimental binding potencies Δ G EXP (the mean absolute deviations | Δ G FEP − Δ G EXP | < 2 kcal/mol) than those Δ G MM-PBSA or Δ G MM-GBSA predicted by the MM-PBSA or MM-GBSA method. Lead L12 had an IC 50 of 8.7 nmol/L and exhibited a different binding pattern in its crystal structure with PDE5 from the famous starting drug tadalafil. Our work provides the first report via the FEP-guided scaffold hopping strategy for potent inhibitor discovery with a novel scaffold, implying that it will have a variety of future applications in rational molecular design and drug discovery. Our work provides the first report about the free energy perturbation (FEP)-guided scaffold hopping strategy (|Δ G FEP –Δ G EXP |< 2 kcal/mol) to discover potent inhibitors with a novel scaffold. [Display omitted] [ABSTRACT FROM AUTHOR]

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, IC 50 = 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. A potent and highly selective PDE10A inhibitor, 14 ·3HCl (IC 50 = 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 [ABSTRACT FROM AUTHOR]

The ethanolic extract of Aloe barbadensis Miller leaf skin showed inhibitory activity against phosphodiesterase-4D (PDE4D), which is a therapeutic target of inflammatory disease. Subsequent bioassay-guided fractionation led to the isolation of two new anthrones, 6′- O -acetyl-aloin B ( 9 ) and 6′- O -acetyl-aloin A ( 11 ), one new chromone, aloeresin K ( 8 ), together with thirteen known compounds. Their chemical structures were elucidated by spectroscopic methods including UV, IR, 1D and 2D NMR, and HRMS. All of the isolates were screened for their inhibitory activity against PDE4D using tritium-labeled adenosine 3′,5′-cyclic monophosphate ( 3 H-cAMP) as substrate. Compounds 13 and 14 were identified as PDE4D inhibitors, with their IC 50 values of 9.25 and 4.42 μM, respectively. These achievements can provide evidences for the use of A. barbadensis leaf skin as functional feed additives for anti-inflammatory purpose. [ABSTRACT FROM AUTHOR]

Abstract: Bioassay-guided fractionation of the ethanol extract of the Chinese folk medicine Crotalaria ferruginea led to the isolation of a new isoflavonoid, 4′-hydroxy-2′-methylalpinum-isoflavone (1), and eight known analogs (2–9). Their structures were elucidated by spectroscopic analysis. Compounds 1, 2, 5, and 8 showed inhibitory activities against phosphodiesterase-4 (PDE4), a therapeutic target of asthma, with IC50 values ranging from 2.57 to 8.94μM. The possible action mechanism and the structure–activity relationship (SAR) of the active isoflavonoids were explored by using molecular docking and molecular dynamics (MD) simulation methods. Our study herein may explain the anti-inflammatory function of this plant in Chinese folk medicine. [Copyright &y& Elsevier]

SelaginpulvilinsA–D (1–4), four new phenolswith an unprecedented 9,9-diphenyl-1-(phenylethynyl)-9H-fluorene skeleton, together with four known selaginellins(5–8) were isolated from Selaginella pulvinata. Their structures were elucidatedby spectroscopic analysis and chemical correlation. The structureof 1was confirmed by single-crystal X-ray diffraction.Compounds 1–8exhibited remarkableinhibitory activities (IC50values in the range of 0.11–5.13μM) against phosphodiesterase-4 (PDE4), a drug target for thetreatment of asthma and chronic obstructive pulmonary disease. [ABSTRACT FROM AUTHOR]

[Display omitted] • Structural optimizations of Moracin M resulted in several potent PDE4 inhibitors. • Lead L13 has an IC 50 of 36 ± 7 nM with remarkable selectivity. • L13 exhibits considerable drug-like profile. • L13 ·citrate displayed more significant anti-IPF effect than the marketed drug pirfenidone in vivo. • Docking studies on PDE4- L13 interactions mainly agree with the experimental results. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and high mortality lung disease. Although the antifibrotic drugs pirfenidone and nintedanib could slow the rate of lung function decline, the usual course of the condition is inexorably to respiratory failure and death. Therefore, new approaches and novel therapeutic drugs for the treatment of IPF are urgently needed. And the selective PDE4 inhibitor has in vivo and in vitro anti-fibrotic effects in IPF models. But the clinical application of most PDE4 inhibitors are limited by their unexpected and severe side effects such as nausea, vomiting, and diarrhea. Herein, structure-based optimizations of the natural product Moracin M resulted in a novel a novel series of 2-arylbenzofurans as potent PDE4 inhibitors. The most potent inhibitor L13 has an IC 50 of 36 ± 7 nM with remarkable selectivity across the PDE families and administration of L13 ·citrate (10.0 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to pirfenidone (300 mg/kg) in a bleomycin-induced IPF mice model, indicate that L13 is a potential lead for the treatment of IPF. [ABSTRACT FROM AUTHOR]

Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC 50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a , originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent. [Display omitted] • Lead 22d had maintained the safety superiority of the mangostanin scaffold (emetic dose >10 mg/kg) and simulated the key interactions between PDE4 and highly potent roflumilast (inhibitory IC 50 of 3.5 nM). • Lead 22d was a potential novel agent for treatment of Inflammatory Bowel Diseases. • Their co-crystal structures revealed that interacting with the M pocket was an effective strategy to improve the potencies of PDE4 inhibitors. [ABSTRACT FROM AUTHOR]

[Display omitted] Phosphodiesterase-4 (PDE4) is an important drug target for inflammatory diseases. Previously, we identified a series of novel PDE4 inhibitors derived from the natural Toddacoumalone, among which the hit compound 2 with a naphthyridine scaffold showed moderate potency with the IC 50 value of 400 nM. Based on the co-crystal structure of PDE4D- 2 , further structural optimizations and structure–activity relationship studies led to a highly potent PDE4 inhibitor 23a with the IC 50 value of 0.25 nM and excellent selectivity profiles over other PDEs (>4000-fold). The co-crystal structure of PDE4D- 23a elucidated that 23a has strong interactions with the M and Q pocket of PDE4D. Importantly, compound 23a significantly inhibits the release of inflammatory cytokines TNF- α and IL-6 in lipopolysaccharide-stimulated RAW264.7 cells. Thus, compound 23a with a naphthyridine scaffold is a promising PDE4 inhibitor for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

The article presents a chemical formula related to the article "Selaginpulvilins A-D, New Phosphodiesterase-4 Inhibitors with an Unprecedented Skeleton from Selaginella pulvinata" by X. Liu and others, published in the periodical "Organic Letters" in 2014.