ABSTRACT
Dexamethasone (DEX) is a potent synthetic glucocorticoid used for the treatment of variety of inflammatory and immune-mediated disorders. The RECOVERY clinical trial revealed benefits of DEX therapy in COVID-19 patients. Severe SARS-CoV-2 infection leads to an excessive inflammatory reaction commonly known as a cytokine release syndrome that is associated with activation of the toll like receptor 4 (TLR4) signaling pathway. The possible mechanism of action of DEX in the treatment of COVID-19 is related to its anti-inflammatory activity arising from inhibition of cytokine production but may be also attributed to its influence on immune cell trafficking and turnover. This study, by means of pharmacokinetic/pharmacodynamic modeling, aimed at the comprehensive quantitative assessment of DEX effects in lipopolysaccharide-challenged rats and to describe interrelations among relevant signaling molecules in this animal model of cytokine release syndrome induced by activation of TLR4 pathway. DEX was administered in a range of doses from 0.005 to 2.25 mg·kg-1 in LPS-challenged rats. Serum DEX, corticosterone (CST), tumor necrosis factor α, interleukin-6, and nitric oxide as well as lymphocyte and granulocyte counts in peripheral blood were quantified at different time points. A minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/PD) model was proposed characterizing the time courses of plasma DEX and the investigated biomarkers. A high but not complete inhibition of production of inflammatory mediators and CST was produced in vivo by DEX. The mPBPK/PD model, upon translation to humans, may help to optimize DEX therapy in patients with diseases associated with excessive production of inflammatory mediators, such as COVID-19. SIGNIFICANCE STATEMENT: A mPBPK/PD model was developed to describe concentration-time profiles of plasma DEX, mediators of inflammation, and immune cell trafficking and turnover in LPS-challenged rats. Interrelations among DEX and relevant biomarkers were reflected in the mechanistic model structure. The mPBPK/PD model enabled quantitative assessment of in vivo potency of DEX and, upon translation to humans, may help optimize dosing regimens of DEX for the treatment of immune-related conditions associated with exaggerated immune response.
Subject(s)
COVID-19 , Lipopolysaccharides , Humans , Rats , Animals , Dexamethasone/pharmacology , Toll-Like Receptor 4 , Cytokine Release Syndrome/drug therapy , COVID-19 Drug Treatment , SARS-CoV-2 , Anti-Inflammatory Agents/pharmacology , Inflammation/drug therapy , Immunity , Inflammation MediatorsABSTRACT
The platelet aggregation inhibitory activity of selected xanthine-based adenosine A2A and A2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A2B receptor antagonist PSB-603 and the A2A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke.
Subject(s)
Atherosclerosis , Blood Platelets , Animals , Rats , Xanthine/pharmacology , AdenosineABSTRACT
Autoimmune hepatitis (AIH) is a life-threatening disorder currently treated with nonspecific immunosuppressive drugs. It is postulated that phosphodiesterase (PDE) inhibitors, as agents exerting anti-inflammatory and immunomodulatory activities, may constitute a possible treatment of autoimmune disorders. This study develops a pharmacokinetic/pharmacodynamic (PK/PD) model to assess the effects of PDE-selective inhibitors, namely, cilostazol (PDE3), rolipram (PDE4), and BRL-50481 (PDE7), in a mouse model of AIH. The pharmacokinetics of the PDE inhibitors (PDEi) were assessed in male BALB/c mice after intraperitoneal administration. In pharmacodynamic studies, mice received PDEi and AIH was induced in these animals by intravenous injection of concanavalin A (ConA). Serum drug concentrations, tumor necrosis factor α (TNFα), interleukin 17 (IL-17), and aminotransferase activities were quantified. The PK/PD analysis was performed using ADAPT5 software. The PK/PD model assumes inhibition of cAMP hydrolysis in T cells by PDEi, ConA-triggered formation of TNFα and IL-17, suppression of TNFα and IL-17 production by cAMP, and stimulatory effects of TNFα and IL-17 on the hepatic release of aminotransferases. Selective blockage of PDE4 leads to the highest inhibition of cAMP degradation in T cells and amelioration of disease outcomes. However, inhibition of both PDE3 and PDE7 also contribute to this effect. The proposed PK/PD model may be used to assess and predict the activities of novel PDEi and their combinations in ConA-induced hepatitis. A balanced suppression of different types of PDE appears to be a promising treatment option for AIH; however, this hypothesis warrants testing in humans based on translation of the PK/PD model into clinical settings. SIGNIFICANCE STATEMENT: A novel PK/PD model of PDE inhibitor effects in mice with ConA-induced autoimmune hepatitis was developed involving a mechanistic component describing changes in cAMP concentrations in mouse T cells. According to model predictions, inhibition of PDE4 in T cells causes the highest cAMP elevation in T cells, but suppression of PDE3 and PDE7 also contribute to this effect. A balanced inhibition of PDE3, PDE4, and PDE7 appears to be a promising treatment strategy for AIH.
Subject(s)
Hepatitis, Autoimmune , Phosphodiesterase Inhibitors , 3',5'-Cyclic-AMP Phosphodiesterases , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Disease Models, Animal , Hepatitis, Autoimmune/drug therapy , Interleukin-17 , Male , Mice , Mice, Inbred BALB C , Phosphodiesterase 3 Inhibitors , Phosphodiesterase Inhibitors/pharmacology , Tumor Necrosis Factor-alphaABSTRACT
Phosphodiesterase (PDE) inhibitors are currently an extensively studied group of compounds that can bring many benefits in the treatment of various inflammatory and fibrotic diseases, including asthma. Herein, we describe a series of novel N'-phenyl- or N'-benzylbutanamide and N'-arylidenebutanehydrazide derivatives of 8-aminopurine-2,6-dione (27-43) and characterized them as prominent pan-PDE inhibitors. Most of the compounds exhibited antioxidant and anti-inflammatory activity in lipopolysaccharide (LPS)-induced murine macrophages RAW264.7. The most active compounds (32-35 and 38) were evaluated in human bronchial epithelial cells (HBECs) derived from asthmatics. To better map the bronchial microenvironment in asthma, HBECs after exposure to selected 8-aminopurine-2,6-dione derivatives were incubated in the presence of two proinflammatory and/or profibrotic factors: transforming growth factor type ß (TGF-ß) and interleukin 13 (IL-13). Compounds 32-35 and 38 significantly reduced both IL-13- and TGF-ß-induced expression of proinflammatory and profibrotic mediators, respectively. Detailed analysis of their inhibition preferences for selected PDEs showed high affinity for isoenzymes important in the pathogenesis of asthma, including PDE1, PDE3, PDE4, PDE7, and PDE8. The presented data confirm that structural modifications within the 7 and 8 positions of the purine-2,6-dione core result in obtaining preferable pan-PDE inhibitors which in turn exert an excellent anti-inflammatory and anti-fibrotic effect in the bronchial epithelial cells derived from asthmatic patients. This dual-acting pan-PDE inhibitors constitute interesting and promising lead structures for further anti-asthmatic agent discovery.
Subject(s)
Anti-Asthmatic Agents/pharmacology , Anti-Inflammatory Agents/pharmacology , Antifibrotic Agents/pharmacology , Antioxidants/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Animals , Anti-Asthmatic Agents/chemical synthesis , Anti-Asthmatic Agents/chemistry , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Antifibrotic Agents/chemical synthesis , Antifibrotic Agents/chemistry , Antioxidants/chemical synthesis , Antioxidants/chemistry , Humans , Mice , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/chemistry , RAW 264.7 CellsABSTRACT
PURPOSE: This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. METHODS: Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. RESULTS: GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. CONCLUSIONS: PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.
ABSTRACT
There was a mistake in the unit of clearance (Cl) in Table II. In addition, the descriptions of V1(ROL) and V1(GRMS-55) were imprecise and the reference number in the footnote below this table should be (9). The corrected Table appears below.
ABSTRACT
Phosphodiesterase (PDE) inhibitors are currently a widespread and extensively studied group of anti-inflammatory and anti-fibrotic compounds which may find use in the treatment of numerous lung diseases, including asthma and chronic obstructive pulmonary disease. Several PDE inhibitors are currently in clinical development, and some of them, e.g., roflumilast, are already recommended for clinical use. Due to numerous reports indicating that elevated intracellular cAMP levels may contribute to the alleviation of inflammation and airway fibrosis, new and effective PDE inhibitors are constantly being sought. Recently, a group of 7,8-disubstituted purine-2,6-dione derivatives, representing a novel and prominent pan-PDE inhibitors has been synthesized. Some of them were reported to modulate transient receptor potential ankyrin 1 (TRPA1) ion channels as well. In this study, we investigated the effect of selected derivatives (832-a pan-PDE inhibitor, 869-a TRPA1 modulator, and 145-a pan-PDE inhibitor and a weak TRPA1 modulator) on cellular responses related to airway remodeling using MRC-5 human lung fibroblasts. Compound 145 exerted the most considerable effect in limiting fibroblast to myofibroblasts transition (FMT) as well as proliferation, migration, and contraction. The effect of this compound appeared to depend mainly on its strong PDE inhibitory properties, and not on its effects on TRPA1 modulation. The strong anti-remodeling effects of 145 required activation of the cAMP/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway leading to inhibition of transforming growth factor type ß1 (TGF-ß1) and Smad-dependent signaling in MRC-5 cells. These data suggest that the TGF-ß pathway is a major target for PDE inhibitors leading to inhibitory effects on cell responses involved in airway remodeling. These potent, pan-PDE inhibitors from the group of 7,8-disubstituted purine-2,6-dione derivatives, thus represent promising anti-remodeling drug candidates for further research.
Subject(s)
Cyclic AMP-Dependent Protein Kinases/metabolism , Cyclic AMP/metabolism , Fibroblasts/drug effects , Lung/drug effects , Phosphodiesterase Inhibitors/pharmacology , Transforming Growth Factor beta1/metabolism , 3',5'-Cyclic-AMP Phosphodiesterases/metabolism , Calcium/metabolism , Cell Movement , Cell Proliferation , Cell Survival , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , Drug Design , Drug Evaluation, Preclinical , Fibroblasts/metabolism , Fibrosis , Humans , Lung/metabolism , Myofibroblasts/metabolism , Signal Transduction , TRPA1 Cation Channel/metabolismABSTRACT
1. Despite the number of favourable properties of lisofylline (LSF), clinical trials on this compound have not yielded the expected results yet. 2. The aims of this study were to evaluate the pharmacokinetics of LSF enantiomers in rats following intravenous, oral and subcutaneous administration of (±)-LSF and to assess the influence of experimental inflammatory disorders, such as multiple organ dysfunction syndrome and severe sepsis on LSF pharmacokinetics. 3. In addition, based on the results obtained an attempt was made to elucidate the possible reasons for the failure of LSF therapy in clinical trials carried out in patients with severe inflammatory disorders. 4. A subcutaneous route of (±)-LSF administration to rats is more favourable than an oral one due to a high bioavailability and a fast absorption of both LSF enantiomers. Pharmacokinetics of LSF in rats is significantly influenced by inflammatory diseases. Too low LSF serum levels might have been one of the reasons for clinical trial failures. A long-term i.v. infusion of LSF seems to be more effective compared to short-term multiple infusions that were used in clinical trials, as it may provide concentrations above IC50 for inhibition of both TNF-alpha release and cAMP degradation in serum for a longer period of time.
Subject(s)
Pentoxifylline/analogs & derivatives , Administration, Intravenous , Administration, Oral , Animals , Biological Availability , Cyclic AMP/metabolism , Drug Evaluation, Preclinical , Humans , Injections, Subcutaneous , Male , Pentoxifylline/pharmacokinetics , Pentoxifylline/pharmacology , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/bloodABSTRACT
Dexamethasone (DEX) given at a dose of 6 mg once-daily for 10 days is a recommended dosing regimen in patients with coronavirus disease 2019 (COVID-19) requiring oxygen therapy. We developed a population pharmacokinetic and pharmacodynamic (PopPK/PD) model of DEX anti-inflammatory effects in COVID-19 and provide simulations comparing the expected efficacy of four dosing regimens of DEX. Nonlinear mixed-effects modeling and simulations were performed using Monolix Suite version 2021R1 (Lixoft, France). Published data for DEX PK in patients with COVID-19 exhibited moderate variability with a clearance of about half that in healthy adults. No accumulation of the drug was expected even with daily oral doses of 12 mg. Indirect effect models of DEX inhibition of TNFα, IL-6, and CRP plasma concentrations were enacted and simulations performed for DEX given at 1.5, 3, 6, and 12 mg daily for 10 days. The numbers of individuals that achieved specified reductions in inflammatory biomarkers were compared among the treatment groups. The simulations indicate the need for 6 or 12 mg daily doses of DEX for 10 days for simultaneous reductions in TNFα, IL-6, and CRP. Possibly beneficial is DEX given at a dose of 12 mg compared to 6 mg. The PopPK/PD model may be useful in the assessment of other anti-inflammatory compounds as well as drug combinations in the treatment of cytokine storms.
Subject(s)
COVID-19 , Tumor Necrosis Factor-alpha , Adult , Humans , Interleukin-6 , COVID-19 Drug Treatment , Anti-Inflammatory Agents , Dexamethasone/pharmacokinetics , Dose-Response Relationship, DrugABSTRACT
Itch and pain are closely related but distinct sensations that share largely overlapping mediators and receptors. We hypothesized that the novel, multi-target compound E153 has the potential to attenuate pain and pruritus of different origins. After the evaluation of sigma receptor affinity and pharmacokinetic studies, we tested the compound using different procedures and models of pain and pruritus. Additionally, we used pharmacological tools, such as PRE-084, RAMH, JNJ 5207852, and S1RA, to precisely determine the role of histamine H3 and sigma 1 receptors in the analgesic and antipruritic effects of the compound. In vitro studies revealed that the test compound had potent affinity for sigma 1 and sigma 2 receptors, moderate affinity for opioid kappa receptors, and no affinity for delta or µ receptors. Pharmacokinetic studies showed that after intraperitoneal administration, the compound was present at high concentrations in both the peripheral tissues and the central nervous system. The blood-brain barrier-penetrating properties indicate its ability to act centrally at the levels of the brain and spinal cord. Furthermore, the test compound attenuated different types of pain, including acute, inflammatory, and neuropathic. It also showed a broad spectrum of antipruritic activity, attenuating histamine-dependent and histamine-independent itching. Finally, we proved that antagonism of both sigma 1 and histamine H3 receptors is involved in the analgesic activity of the compound, while the antipruritic effect to a greater extent depends on sigma 1 antagonism.
ABSTRACT
Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34, being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were utilized to assess the efficacy of this compound, and its pharmacokinetics was investigated in mice and rats. A new PK/PD disease progression model of compound 34 was developed that satisfactorily predicted the clinical score-time courses in mice with experimental encephalomyelitis that is an animal model of MS. Compound 34 displayed a high efficacy in all three animal models of ADs. Simultaneous inhibition of PDE types located in immune cells may constitute an alternative treatment strategy of ADs. The PK/PD encephalomyelitis and arthritis progression models presented in this study may be used in future preclinical research, and, upon modifications, may enable translation of the results of preclinical investigations into the clinical settings.
ABSTRACT
BACKGROUND: To verify the validity of the proposed pain treatment approach, which is based on concomitant blocking of the Transient Receptor Potential Ankyrin 1 (TRPA1) channel and phosphodiesterases (PDEs) 4B/7A activity, we continued our pharmacological studies on 8-alkoxypurine-2,6-diones selected based on previous in vitro screening. METHODS: Derivatives 17, 31, and 36 were pharmacologically evaluated in vivo using the formalin test and oxaliplatin-induced neuropathic pain: the von Frey and the cold plate tests, and in the carrageenan-induced edema model. Compound 36, which turned out to be the most promising, was further evaluated in the collagen-induced arthritis model. The pharmacokinetic parameters of this compound were also estimated. RESULTS: All the tested compounds exhibited significant analgesic and anti-inflammatory activities. Compound 36 was additionally characterized by an antiarthritic effect and showed a favorable pharmacokinetic profile in rats. CONCLUSION: The compounds evaluated in this study represent a new class of derivatives with analgesic and anti-inflammatory activities that involve TRPA1 antagonism and PDE4/7 inhibition.
Subject(s)
Ankyrins , Transient Receptor Potential Channels , Animals , Rats , TRPA1 Cation Channel , Carrageenan , Oxaliplatin , Analgesics/pharmacology , Analgesics/therapeutic use , Anti-Inflammatory Agents/pharmacology , Purines/pharmacology , Phosphoric Diester HydrolasesABSTRACT
This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.
ABSTRACT
Aims: 5-HT1A receptor antagonists constitute a potential group of drugs in the treatment of CNS diseases. The aim of this study was to search for new procognitive and antidepressant drugs among amide derivatives of aminoalkanoic acids with 5-HT1A receptor antagonistic properties. Materials & methods: Thirty-three amides were designed and evaluated in silico for their drug-likeness. The synthesized compounds were tested in vitro for their 5-HT1A receptor affinity and functional profile. Moreover, their selectivity over 5-HT7, 5-HT2A and D2 receptors and ability to inhibit phosphodiesterases were evaluated. Results: A selected 5-HT1A receptor antagonist 20 (Ki = 35 nM, Kb = 4.9 nM) showed procognitive and antidepressant activity in vivo. Conclusion: Novel 5-HT1A receptor antagonists were discovered and shown as potential psychotropic drugs.
Subject(s)
Amides/chemical synthesis , Antidepressive Agents/chemical synthesis , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Antagonists/chemical synthesis , Amides/pharmacology , Animals , Antidepressive Agents/pharmacology , Behavior, Animal , Drug Design , Humans , Male , Models, Molecular , Phosphoric Diester Hydrolases/metabolism , Protein Binding , Rats, Wistar , Receptor, Serotonin, 5-HT2A/metabolism , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Species Specificity , Structure-Activity RelationshipABSTRACT
Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Autoimmune Diseases/drug therapy , Imidazoles/therapeutic use , Inflammation/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Pyridines/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Disease Models, Animal , Female , Humans , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Male , Mice, Inbred BALB C , Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/therapeutic use , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/pharmacokinetics , Phosphodiesterase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats, WistarABSTRACT
BACKGROUND: There is currently no drug that slows the process of neurodegeneration or alleviates the cognitive and depressive symptoms in patients with Alzheimer's disease. Due to the increasing number of Alzheimer's patients, there is an urgent need to develop novel drugs with neuroprotective, procognitive, and antidepressant properties. OBJECTIVE: The aim of this study was to design, synthesize, and evaluate novel aminoalkanamides with serotonin 5-HT1A/5-HT;7 receptor affinity and phosphodiesterase (PDE) inhibitory activity as a new approach to combat neurodegeneration and symptoms of Alzheimer's disease. METHODS: The newly designed compounds were synthesized using classical methods of organic chemistry and tested in vitro for their receptor affinity, functional profile, enzyme inhibition, and ADME properties. The neuroprotective effect against H2O2-induced increase of reactive oxygen species level was tested in SH-SY5Y cells. The novel object recognition and forced swimming tests were used to evaluate the procognitive and antidepressant activity, respectively. RESULTS: Synthesized aminoalkanamides were characterized as potent 5-HT1Areceptor antagonists with additional 5-HT7 receptor antagonistic properties and PDE4B inhibitory activity. Selected compound 15 showed neuroprotective, procognitive, and antidepressant properties. In addition, compound 15 revealed suitable ADME properties expressed as good membrane permeability and high metabolic stability. CONCLUSION: This study revealed a new class of compounds that may be useful in the search for an effective drug in the alleviation of neurodegeneration and symptoms of Alzheimer's disease.
Subject(s)
Alzheimer Disease , Alzheimer Disease/drug therapy , Antidepressive Agents/therapeutic use , Humans , Hydrogen Peroxide/therapeutic use , Receptors, Serotonin , SerotoninABSTRACT
A library of novel anilide and benzylamide derivatives of ω-(4-(2-methoxyphenyl)piperazin-1-yl)alkanoic acids as combined 5-HT1A/5-HT7 receptor ligands and phosphodiesterase PDE4B/PDE7A inhibitors was designed using a structure-based drug design approach. The in vitro studies of 33 newly synthesized compounds (7-39) allowed us to identify 22 as the most promising multifunctional 5-HT1A/5-HT7 receptor antagonist (5-HT1AKi = 8 nM, Kb = 0.04 nM; 5-HT7Ki = 451 nM, Kb = 460 nM) with PDE4B/PDE7A inhibitory activity (PDE4B IC50 = 80.4 µM; PDE7A IC50 = 151.3 µM). Compound 22 exerted a very good ability to passively penetrate through biological membranes and a high metabolic stability in vitro. Moreover, the pharmacological evaluation of 22 showed its procognitive and antidepressant properties in rat behavioral tests. Compound 22 at a dose of 3 mg/kg (i.p.) significantly reversed MK-801-induced episodic memory deficits in the novel object recognition test, while at a dose of 10 mg/kg (i.p.) reduced the immobility time of animals (by about 34%) in the forced swimming test. The antidepressant-like effect produced by compound 22 was stronger than that of escitalopram used as a reference drug. This study opens a new perspective in the search for efficacious drugs for the treatment of cognitive and depressive disorders.
Subject(s)
Anilides/pharmacology , Central Nervous System Agents/pharmacology , Phosphodiesterase 4 Inhibitors/pharmacology , Piperazines/pharmacology , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Anilides/chemical synthesis , Anilides/metabolism , Animals , CHO Cells , Central Nervous System Agents/chemical synthesis , Central Nervous System Agents/metabolism , Cricetulus , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 7/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 7/metabolism , HEK293 Cells , Humans , Male , Microsomes, Liver/metabolism , Molecular Docking Simulation , Molecular Structure , Open Field Test/drug effects , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/metabolism , Piperazines/chemical synthesis , Piperazines/metabolism , Protein Binding , Rats, Wistar , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Serotonin/metabolism , Serotonin 5-HT1 Receptor Antagonists/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists/metabolism , Sf9 Cells , Structure-Activity RelationshipABSTRACT
Schizophrenia is a debilitating mental disorder with relatively high prevalence (~1%), during which positive manifestations (such as psychotic states) and negative symptoms (e.g., a withdrawal from social life) occur. Moreover, some researchers consider cognitive impairment as a distinct domain of schizophrenia symptoms. The imbalance in dopamine activity, namely an excessive release of this neurotransmitter in the striatum and insufficient amounts in the prefrontal cortex is believed to be partially responsible for the occurrence of these groups of manifestations. Second-generation antipsychotics are currently the standard treatment of schizophrenia. Nevertheless, the existent treatment is sometimes ineffective and burdened with severe adverse effects, such as extrapyramidal symptoms. Thus, there is an urgent need to search for alternative treatment options of this disease. This review summarizes the results of recent preclinical and clinical studies on phosphodiesterase 10A (PDE10A), which is highly expressed in the mammalian striatum, as a potential drug target for the treatment of schizophrenia. Based on the literature data, not only selective PDE10A inhibitors but also dual PDE2A/10A, and PDE4B/10A inhibitors, as well as multifunctional ligands with a PDE10A inhibitory potency are compounds that may combine antipsychotic, precognitive, and antidepressant functions. Thus, designing such compounds may constitute a new direction of research for new potential medications for schizophrenia. Despite failures of previous clinical trials of selective PDE10A inhibitors for the treatment of schizophrenia, new compounds with this mechanism of action are currently investigated clinically, thus, the search for new inhibitors of PDE10A, both selective and multitarget, is still warranted.
Subject(s)
Central Nervous System Diseases/drug therapy , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/therapeutic use , Phosphoric Diester Hydrolases/metabolism , Schizophrenia/drug therapy , Animals , Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Central Nervous System Diseases/metabolism , Drug Delivery Systems/methods , Humans , Schizophrenia/metabolismABSTRACT
Phosphodiesterase 10A (PDE10A) is a double substrate enzyme that hydrolyzes second messenger molecules such as cyclic-3',5'-adenosine monophosphate (cAMP) and cyclic-3',5'-guanosine monophosphate (cGMP). Through this process, PDE10A controls intracellular signaling pathways in the mammalian brain and peripheral tissues. Pharmacological, biochemical, and anatomical data suggest that disorders in the second messenger system mediated by PDE10A may contribute to impairments in the central nervous system (CNS) function, including cognitive deficits as well as disturbances of behavior, emotion processing, and movement. This review provides a detailed description of PDE10A and the recent advances in the design of selective PDE10A inhibitors. The results of preclinical studies regarding the potential utility of PDE10A inhibitors for the treatment of CNS-related disorders, such as schizophrenia as well as Huntington's and Parkinson's diseases are also summarized.
Subject(s)
Central Nervous System Diseases/drug therapy , Cognition Disorders/drug therapy , Phosphodiesterase Inhibitors/pharmacology , Phosphoric Diester Hydrolases/metabolism , Signal Transduction/drug effects , Animals , Brain/drug effects , Brain/pathology , Central Nervous System Diseases/pathology , Cognition Disorders/pathology , Cyclic AMP/metabolism , Cyclic GMP/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Phosphodiesterase Inhibitors/therapeutic use , Treatment OutcomeABSTRACT
Airway remodelling (AR) is an important pathological feature of chronic asthma and chronic obstructive pulmonary disease. The etiology of AR is complex and involves both lung structural and immune cells. One of the main contributors to airway remodelling is the airway smooth muscle (ASM), which is thickened by asthma, becomes more contractile and produces more extracellular matrix. As a second messenger, adenosine 3',5'-cyclic monophosphate (cAMP) has been shown to contribute to ASM cell (ASMC) relaxation as well as to anti-remodelling effects in ASMC. Phosphodiesterase (PDE) inhibitors have drawn attention as an interesting new group of potential anti-inflammatory and anti-remodelling drugs. Recently, new hydrazide and amide purine-2,6-dione derivatives with anti-inflammatory properties have been synthesized by our team (compounds 1 and 2). We expanded our study of their PDE selectivity profile, ability to increase intracellular cAMP levels, metabolic stability and, above all, their capacity to modulate cell responses associated with ASMC remodelling. The results show that both compounds have subtype specificity for several PDE isoforms (including inhibition of PDE1, PDE3, PDE4 and PDE7). Interestingly, such combined PDE subtype inhibition exerts improved anti-remodelling efficacies against several ASMC-induced responses such as proliferation, contractility, extracellular matrix (ECM) protein expression and migration when compared to other non-selective and selective PDE inhibitors. Our findings open novel perspectives in the search for new chemical entities with dual anti-inflammatory and anti-remodelling profiles in the group of purine-2,6-dione derivatives as broad-spectrum PDE inhibitors.