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ABSTRACTIntroductionPDE2 is a dual-specific enzyme that hydrolyzes two intracellular substrates, cAMP and cGMP. PDE2 is mainly distributed in the brain, which indicates that PDE2 can serve as a potential target for central nervous system diseases without causing other peripheral side effects. Discovery of new mechanisms of PDE2 inhibitors is expected to bring new opportunities for the treatment of central nervous system diseases.Area coveredThis review aims to provide an overview of PDE2 inhibitors reported in patents from 2017 to present.Expert opinionIn recent years, the development of PDE2 inhibitors and their application in the treatment of brain diseases have received much attention. The main reason is the high expression of PDE2 in the brain, which gives PDE2 a natural advantage as a research target for central nervous system diseases. This review summarizes the scaffolds of PDE2 inhibitors reported in various patents since 2017, as well as the scientific issues that need to be addressed in terms of subtype selectivity and metabolic stability, intending to provide insights for the discovery of highly active and selective PDE2 inhibitors in the future.

ABSTRACTIntroductionPhosphodiesterase 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 coveredThis review provides an overview of PDE9 inhibitors in patents from 2018 to the present.Expert opinionOnly 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.

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-205/1186117with 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 13hexhibited the IC50of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13hexerted 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.

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 2gexhibited excellent inhibitory activity against PDE1C (IC50= 10 nM), high selectivity over other PDEs except for PDE4, and weak calcium channel antagonistic activity. Administration of compound 2gexhibited remarkable therapeutic effects in a rat model of pulmonary fibrosis induced by bleomycin and prevented myofibroblast differentiation induced by TGF-β1. The expressions of PDE1B and PDE1C were found to be increased and concentrated in the focus of fibrosis. Compound 2gincreased the levels of 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) in the lungs of rats with pulmonary fibrosis, supporting the fact that the anti-fibrosis effects of 2gwere through the regulation of cAMP and cGMP.

ABSTRACTIntroductionPDE1 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.Area coveredThis review aims to provide an overview of PDE1 inhibitors reported in patents from 2008 to present.Expert opinionAmong 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.

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 LL01led to lead 4a, which exhibited an IC50value of 7.3 nM against PDE9, excellent selectivity against other PDE subfamilies, and remarkable microsomal stability. The cocrystal structure of PDE9 with 4arevealed an important residue, Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration of 4aexerted 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. BVQ1814showed an outstanding binding affinity for PDE10A in vitroand 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.

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, 3abound to PDE8A with a different mode from 3-isobutyl-1-methylxanthine (a pan-PDE inhibitor) and gave a H-bond of 2.7 Å with Tyr748, which possibly interprets the 220-fold selectivity of 3aagainst PDE2A. Additionally, oral administration of compound 3aachieved remarkable therapeutic effects against vascular dementia (VaD), indicating that PDE8 inhibitors could serve as potential anti-VaD agents.

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 3mwith an IC50of 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.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3fwas obtained, exhibiting an IC50value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure–activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

Great attention has been paid to the clinical significance of phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, tadalafil, and vardenafil widely used for erectile dysfunction. However, sildenafil causes side effects on visual functions since it shows similar potencies to inhibit PDE5 and PDE6, whereas tadalafil gives a high selectivity of 1020-fold against PDE6. Till now, their molecular mechanisms of selectivity of PDE5 versus PDE6 have remained unknown in the absence of the crystal structure of PDE6. In order to elucidate its isoform-selective inhibitory mechanism, a 3D model of PDE6 was constructed by homology modeling, and its interaction patterns with tadalafil plus sildenafil were exploited by molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. The present work reveals that tadalafil exhibits a less negative predicted binding free energy of −35.21 kcal/mol with PDE6 compared with the value of −41.12 kcal/mol for PDE5, which suggests that tadalafil prefers PDE5 rather than PDE6 and confers a high selectivity for PDE5 versus PDE6. The binding free energy results for tadalafil were consistent with external bioassay studies (IC50= 5100 and 5 nM toward PDE6 and PDE5, respectively). Two important residues from the Q2pockets (Val782 and Leu804 in PDE5 and their corresponding Val738 and Met760 in PDE6) were further identified to account for the high selectivity of tadalafil for PDE5 versus PDE6. These findings have shed light on the continuous puzzle of why sildenafil (IC50= 74 and 6 nM toward PDE6 and PDE5, respectively) causes visual disorders because of its poor selectivity but tadalafil does not. In addition, the homology model of PDE6 can be used to design more potent and selective second-generation PDE5 inhibitors with less inhibitory potency against PDE6.

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 2with 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.

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 2bwith subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10–2bcomplex revealed an important H-bond interaction between 2band Tyr693. Finally, compound 2bsignificantly 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.

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 (IC50= 0.87 nM, ∼2000-fold improvement in potency) with cocrystal confirmation.

Objective: We aim to provide new insight and scientific evidence for rational design and discovery of phosphodiesterase-9A (PDE9A) inhibitors with remarkable potency and weak side effect to treat CNS diseases such as Alzheimer's disease. Methods: Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of PDE9A inhibitors. Moreover, two different alignment methods, docking-based structural alignment (DCBA) and local lowest energy structure based alignment (LESBA), were employed to scrutinize their effects on the robustness and predictive capability of 3D-QSAR models. Results: The models generated by CoMFA had a cross-validated coefficient (q2) of 0.771 and a regression coefficient (r2) of 0.983. The CoMSIA models had a (q2) of 0.776 and (r2) of 0.960. The external predictive capability of the built models was evaluated by using the test set of nine compounds. From obtained results, the CoMSIA models were found to have highly predictive capability in comparison with CoMFA models. Contour maps of CoMSIA models provided many helpful structural insights, including N1-bulkier hydrophobic group such as cyclopentyl group better filling the metal binding pocket in the PDE9A to show stronger inhibitory activity. Conclusions: Docking-based 3D-QSAR studies is helpful to improve the design of pyrazolopyrimidinone derivatives as PDE9A inhibitors to develop new chemical entities with higher selectivity.

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1H)-ones were designed rationally, leading to compound 10cwith an IC50of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties. Furthermore, we used the lead compound 10cas a chemical tool to explore whether PDE1 could work as a novel potential target for the treatment of inflammatory bowel disease (IBD), a disease which is a chronic, relapsing disorder of the gastrointestinal tract inflammation lacking effective treatment. Our results showed that administration of 10cexerted significant anti-IBD effects in the dextran sodium sulfate-induced mice model and alleviated the inflammatory response, indicating that PDE1 could work as a potent target for IBD.

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.

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 IC50value 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.

Phosphodiesterases (PDEs) are the sole enzymes hydrolyzing the important second messengers cGMP and cAMP and have been identified as therapeutic targets for several diseases. The most successful examples are PDE5 inhibitors (i.e., sildenafil and tadalafil), which have been approved for the treatment of male erectile dysfunction and pulmonary hypertension. However, the side effects mostly due to nonselective inhibition toward other PDE isoforms, set back the clinical usage of PDE5 inhibitors. Until now, the exact catalytic mechanism of the substrate cGMP by PDE5 is still unclear. Herein, the first computational study on the catalytic hydrolysis mechanism of cGMP for PDE5 (catalytic domain) is performed by employing the state-of-the-art ab initio quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. Our simulations show a SN2 type reaction procedure via a highly dissociated transition state with a reaction barrier of 8.88 kcal/mol, which is quite different from the previously suggested hydrolysis mechanism of cAMP for PDE4. Furthermore, the subsequent ligand exchange and the release of the product GMP have also been investigated by binding energy analysis and MD simulations. It is deduced that ligand exchange would be the rate-determining step of the whole reaction, which is consistent with many previous experimental results. The obtained mechanistic insights should be valuable for not only the rational design of more specific inhibitors toward PDE5 but also understanding the general hydrolysis mechanism of cGMP-specific PDEs.

The asymmetric vanadium‐catalyzed oxidation of 1,3‐dithianes from aldehydes and ketones by β‐amino alcohol‐derived Schiff base ligands with two stereogenic centers was investigated. Using aqueous hydrogen peroxide as the oxidant and the Schiff base 3bas a chiral ligand, a variety of 1,3‐dithianes derived from aldehydes were easily converted into the corresponding mono‐sulfoxides in good yields (81–88%) with excellent enantioselectivities (up to 99% ee). Additionally, 99% eewas obtained for the enantioselective vanadium‐catalyzed oxidation of the 1,3‐dithianes derived from ketones. We found a slight kinetic resolution when using a higher ratio of hydrogen peroxide during the oxidation of the aldehyde‐derived 1,3‐dithianes but not in the ketone‐derived 1,3‐dithianes.

Novel Schiff base ligands derived from βamino alcohols with two stereogenic centers were prepared and used in the preparation of optically pure sulfoxides by using aqueous hydrogen peroxide as the oxidant. A variety of sulfides were smoothly converted into the corresponding sulfoxides catalyzed by the chiral vanadium–Schiff base complex. Good yields >80  with excellent enantioselectivities >99  ee were obtained in most cases. © WileyVCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009

A series of sulfonamides (2–4) were prepared from natural amino acids and used as additives in the BINOL‐Ti(OiPr)4catalyzed enantioselective alkynylation of aldehydes. The reactions proceeded smoothly with good yields and very high ee's (up to 99%) in most cases. Chirality 19:638–641, 2007 © 2007 Wiley‐Liss, Inc.

1,3‐Dithiane substrates, derived from aromatic aldehydes, are oxidized to the corresponding sulfoxides with excellent enantioselectivities.

The reaction requires excess tBuOOH to assure high yields.

Optically active diamine PAP with a polyethylene glycol chain attached to one nitrogen is a highly active and enantioselective ligand in the transfer hydrogenation of aromatic ketones.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.