Phosphodiesterase 4 Inhibitor Research Articles

Effect of phosphodiesterase-4 inhibitor rolipram on colonic hypermotility in water avoidance stress rat model.

BackgroundPhosphodiesterase (PDE) inhibition has been reported to play a role in regulating gut motility, but the evidence is insufficient, and the mechanism remains unknown. The aim of this study was to investigate the possible role of phosphodiesterase‐4 (PDE4) inhibitor rolipram in water avoidance stress‐induced colonic hypermotility.MethodsA rat model of irritable bowel syndrome (IBS) with diarrhea (IBS‐D) was established by water avoidance stress (WAS). Intestinal motility was assessed by fecal pellets expulsion per hour. The cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) level in colon tissue were detected using ELISA assay and the Griess test, respectively. Western blotting was performed to assess the protein level of PDE, PKA/p‐CREB, and neuronal nitric oxide synthase (nNOS) in the colon. To determine the role of rolipram in gut motility, the rats of the WAS + Rolipram and Rolipram group were injected with rolipram intraperitoneally. The colonic contractile activity was recorded with a RM6240 multichannel physiological signal system.Key Results: WAS‐induced gastrointestinal hypermotility and increased defecation in rats. After repeated stress, protein levels of PDE4 in the colon were promoted while PKA/p‐CREB and nNOS were highly decreased. cAMP content in colon tissue did not change significantly. However, NO content decreased after WAS, and rolipram partly enhanced NO in WAS‐exposed rats. In addition, intraperitoneal injection of rolipram partly inhibited the colonic motility in vivo. Meanwhile, we observed rolipram inhibited the contraction of colonic smooth muscle strips, and this inhibitory effect was abolished by Nω‐Nitro‐L‐arginine (L‐NNA), a nitric oxide synthase (NOS) inhibitor, tetrodotoxin (TTX), a blocker of neuronal voltage‐dependent Na+ channels, Rp‐Adenosine 3’,5'‐cyclic monophosphorothioate triethylammonium salt hydrate (Rp‐cAMPS), an antagonist of cAMP.Conclusions and Inferences: Rolipram could relieve stress‐induced gastrointestinal hypermotility. This effect may be partly through the cAMP‐PKA‐p‐CREB pathway and NO pathway.

Phosphodiesterase‑4 inhibitors: a review of current developments (2013–2021)

ABSTRACT Introduction Cyclic nucleotide phosphodiesterase 4 (PDE4) is responsible for the hydrolysis of cAMP, which has become an attractive therapeutic target for lung, skin, and severe neurological diseases. Here, we review the current status of development of PDE4 inhibitors since 2013 and discuss the applicability of novel medicinal-chemistry strategies for identifying more efficient and safer inhibitors. Areas covered This review summarizes the clinical development of PDE4 inhibitors from 2013 to 2021, focused on their pharmacophores, the strategies to reduce the side effects of PDE4 inhibitors and the development of subfamily selective PDE4 inhibitors. Expert opinion To date, great efforts have been made in the development of PDE4 inhibitors, and researchers have established a comprehensive preclinical database and collected some promising data from clinical trials. Although four small-molecule PDE4 inhibitors have been approved by FDA for the treatment of human diseases up to now, further development of other reported PDE4 inhibitors with strong potency has been hampered due to the occurrence of severe side effects. There are currently three main strategies for overcoming the dose limitation and systemic side effects, which provide new opportunities for the clinical development of new PDE4 inhibitors.

Insights into the potential of withanolides as Phosphodiesterase-4 (PDE4D) inhibitors

Medicinal herbs have been used as traditional medicines for centuries. The molecular mechanism of action of their bioactive molecules against various diseases or therapeutic targets is still being explored. Here, the active compounds (withanolides) of a well-known Indian medicinal herb, Ashwagandha (Withania somnifera), have been studied for their most potential therapeutic targets and their mechanism of action using ligand-based screening and receptor-based approaches. Ligand-based screening predicted the six top therapeutic targets, namely, Protein kinase C alpha (PRKCA), Protein kinase C delta (PRKCD), Protein kinase C epsilon (PRKCE), Androgenic Receptor (AR), Cycloxygenase-2 (PTGS-2) and Phosphodiesterase-4D (PDE4D). Further, when these predictions were validated using receptor-based studies, i.e. molecular docking, molecular dynamics simulation and free energy calculations, it was found that PDE4D was the most potent target for four withanolides, namely, Withaferin-A, 17-Hydroxywithaferin-A, 27-Hydroxywithanone and Withanolide-R. These compounds had a better binding affinity and similar interactions as that of an already known inhibitor (Zardaverine) of PDE4D. These results warrant further in-vitro and in-vivo investigations to examine their therapeutic potential as an inhibitor of PDE4D. Communicated by Ramaswamy H. Sarma

Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein

We have previously shown that inhibition of cAMP-specific 3′,5′-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 μM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.

Safety Profile and Tolerability of Topical Phosphodiesterase 4 Inhibitors for the Treatment of Atopic Dermatitis: A Systematic Review and Meta-Analysis

ObjectiveEvaluate the safety profile and tolerability of topical phosphodiesterase 4 (PDE4) inhibitors versus vehicle as treatment for atopic dermatitis in published studies.MethodsA search was performed in Medline/PubMed, Web of Science, and Cochrane Library databases on September 27, 2021, by 1 evaluator, without restrictions on publication dates or languages. Terms such as atopic dermatitis, phosphodiesterase 4 inhibitors, calcineurin inhibitors, and randomized controlled trials were included. The database searches were carried out by 1 evaluator. The titles and abstracts were reviewed for the identification and evaluation of potentially eligible studies. Study selection was made by two reviewers, so there was no intra-examiner statistic at the study selection step. The full-text articles were reviewed to determine whether or not they would be included in the systematic review. Global analyses, which included studies with both unclear and low risk of bias and subanalyses of studies with a low risk of bias were performed.ResultsOut of 237 identified articles, 14 clinical trials were included in the meta-analysis. In global analyses of studies with low and unclear risk of bias, topical treatment with PDE4 inhibitors did not differ from vehicle treatment in global treatment emergent adverse events (relative risk = 0.99; 95% CI, 0.87–1.14; P = 0.94) or in serious emergent adverse events appearance (relative risk = 0.92; 95% CI, 0.39–2.20; P = 0.86). In subanalyses of studies with a low risk of bias, a reduced rate of atopic dermatitis exacerbation was observed in PDE4 inhibitors compared with the vehicle (relative risk = 0.62; 95% CI, 0.39-0.98; P = 0.04) and risk of pain at the application site was confirmed (relative risk = 2.59; 95% CI, 1.27–5.28; P = 0.01).ConclusionsPDE4 inhibitors did not show differences from vehicle treatment in treatment emergent adverse events or serious emergent adverse events incidence. In studies with low risk of bias, PDE4 inhibitors had a statistically significant risk of producing pain and reduced occurrence of atopic dermatitis exacerbation.

Phosphodiesterase 4 (PDE4) gene expression in atopic dermatitis patients, before and after treatment with topical mometasone cream.

Atopic dermatitis (AD) is a chronic pruritic inflammatory dermatosis. Phosphodiesterases (PDEs) are a superfamily of enzymes that catalyse the hydrolysis of cyclic AMP (cAMP), a second messenger that controls key cellular functions, into its inactive forms. Selective inhibitors of PDE4, a cAMP-specific PDE, serve as potent anti-inflammatory agents. To measure PDE4 gene expression in patients with AD before and after treatment with topical mometasone cream, in comparison to controls Twenty patients with acute and subacute AD were investigated. Skin biopsies before and after treatment were obtained for evaluation of PDE4 expression level by RT-PCR The level of PDE4 mRNA was significantly higher in AD patients either before or after treatment compared to controls (p < 0.001), and the level of PDE4 mRNA in AD patients significantly decreased following treatment (p < 0.001) Our study indicates that there is an increased level of PDE4 in AD lesions, suggesting that PDE4 plays an important role in the pathogenesis of AD. Targeting PDE4 (using PDE4 inhibitors) may herald a new era in the treatment of AD.

Comparative risk of herpes zoster in patients with psoriatic disease on systemic treatments: a systematic review and network meta-analysis.

Background:Numerous previous studies have examined risk of herpes zoster (HZ) in psoriatic disease; however, the results of these studies are conflicting and the relative risks associated with different treatments remain largely unknown. In this meta-analysis, we examined the relative risk of HZ associated with systemic treatments for psoriatic disease.Methods:PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched to identify relevant English-language studies published up to April 2021. Data were extracted using a standardized data extraction form. Network meta-analyses (NMA) was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. We examined the differences in HZ risk (incidence rate ratio; IRR) between treatments using a random-effects model for direct pairwise comparisons and NMA. The surface under the cumulative ranking area was calculated to rank the HZ risk for each treatment condition.Results:This study analyzed 13 studies including 19 treatment arms involving a total of 443,104 patients with psoriatic disease. Corticosteroids (CS) [IRR, 2.56; 95% confidence interval (CI), 1.59–4.13], a Janus kinase inhibitor (JAKi; tofacitinib) (IRR, 2.34; 95% CI, 1.03–5.32), infliximab (IRR, 2.32; 95% CI, 1.27–4.21), conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) + CS (IRR, 2.26; 95% CI, 1.23–4.17), anti-tumor necrosis factor-α (anti-TNF-α) + csDMARDs and/or CS (IRR, 2.13; 95% CI, 1.38–3.31), csDMARDs (IRR, 1.62; 95% CI, 1.18–2.22), and anti-TNF-α except infliximab (IRR, 1.61; 95% CI, 1.13–2.30) were all associated with a significantly higher HZ risk compared to controls. CS treatment possessed the highest HZ risk, followed by infliximab and JAKi (tofacitinib). Phosphodiesterase-4 inhibitor, anti-interleukin-17, -23 or -12/23, phototherapy, and acitretin showed a risk similar to controls without significant differences.Conclusion:The NMA demonstrated CS, infliximab, and JAKi (tofacitinib), and several combination treatments were associated with higher HZ risk in patients with psoriasis and psoriatic arthritis. Differences in HZ risk should be taken into consideration when considering optimal psoriasis treatment.

Apremilast Prolongs the Time to First Biologic Therapy in Japanese Patients with Psoriasis

IntroductionBiologic agents are used in patients with severe psoriasis who have not adequately responded to existing conventional systemic therapies. However, only a limited number of medical institutions in Japan are approved to use them, and their relatively high cost represents a substantial burden to patients. Apremilast is an oral phosphodiesterase-4 inhibitor approved in Japan for the treatment of psoriasis vulgaris in adult patients with an inadequate response to topical therapies and psoriatic arthritis in adult patients with active disease. To date, a large-scale real-world study of treatment patterns and costs associated with apremilast in Japan has not been conducted. The objective of this study was to assess whether apremilast can prolong time to first biologic therapy use and decrease total medical cost.MethodsUsing the Medical Data Vision hospital-based claims database, 506 psoriasis patients were propensity score matched and analyzed (apremilast: n = 253; non-apremilast: n = 253).ResultsThe incidence rate of first biologic therapy use per 1000 patient-years was significantly lower in the apremilast group than in the non-apremilast group (30.3 vs. 107.6; P < 0.001), and the total medical costs per month were significantly lower in the apremilast group than in the non-apremilast group (76,594 yen/month vs. 102,411 yen/month, P < 0.001). In a sensitivity analysis of a propensity-score-matched subset of eligible patients prescribed biologics during the follow-up period (apremilast: n = 14; non-apremilast: n = 14), the incidence of first biologic therapy use was 2,797.6 per 1000 patient-years (95% CI: 1,656.9, 4,723.6) in the non-apremilast group and 856.1 per 1000 patient-years (95% CI: 507.0, 1,445.5) in the apremilast group.ConclusionThese results suggest that apremilast prolongs the time to first biologic therapy use in patients with psoriasis, thereby reducing the total medical cost and decreasing the economic burden on patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00659-w.

Effect of the inhalation inhibitor PDE-4 CHF6001 on some pathogenetic links in chronic obstructive pulmonary disease development

CHF6001 is a new inhaled phosphodiesterase-4 inhibitor that is safe and well tolerated by both healthy people and patients with bronchial asthma. The effect of CHF6001, in addition to standard triple therapy for chronic obstructive pulmonary disease, was evaluated on some inflammatory markers in induced sputum and blood in 61 patients (54 completed the study) with chronic obstructive pulmonary disease and chronic bronchitis. From October 2016 to November 2017, a multicenter, three-period (every 32 days), tripartite, placebo-controlled, double-blind, complete block cross-sectional study was conducted in Great Britain and Germany. Patients were treated by CHF6001 at doses of 800 or 1600 g, or the corresponding placebo using the dry powder inhaler NEXThaler. The induced sputum was collected on day 1 before the treatment and days 20, 26, and 32 after the treatment. Blood was also collected on day 1 before the treatment and day 32 before and after the treatment. Result analyses took into account the inflammatory biomarkers in induced sputum and blood, respiratory function, and symptoms and side effects. CHF6001, which supplements triple therapy in patients with moderate to severe chronic obstructive pulmonary disease and chronic bronchitis, was well tolerated and significantly reduces the number of key biomarkers of airway inflammation in sputum and blood after 32 days of treatment. CHF6001, administered by inhalation, creates a high therapeutic concentration in the lungs compared with other systemic phosphodiesterase-4 inhibitors and improves the therapeutic index due to anti-inflammatory effects while minimizing the possible side effects typical of the latter.

Matching-Adjusted Indirect Comparison of Crisaborole Ointment 2% vs. Topical Calcineurin Inhibitors in the Treatment of Patients with Mild-to-Moderate Atopic Dermatitis

IntroductionCrisaborole topical ointment, 2%, is a nonsteroidal, topical anti-inflammatory phosphodiesterase-4 (PDE4) inhibitor that is approved for the treatment of mild-to-moderate atopic dermatitis (AD). The objective of the current analysis was to compare the efficacy of crisaborole 2% relative to pimecrolimus 1%, tacrolimus 0.03% and tacrolimus 0.1% in patients aged ≥ 2 years with mild-to-moderate AD by comparing improvement in Investigator’s Static Global Assessment scores ( (ISGA scores of 0/1 indicating “clear or almost clear”). ISGA was selected as the primary efficacy outcome given the US Food and Drug Administration’s recommendations on the use of ISGA for assessment of global severity in AD and to align with efficacy measurements in the crisaborole registration trials. Safety endpoints could not be analyzed due to differences in outcome definitions across studies.MethodsEfficacy of crisaborole was evaluated using individual patient data (IPD) from two pivotal phase III randomized controlled trials (RCTs), and efficacy of comparators was evaluated using published RCTs included in a previous network meta-analysis. Vehicle controls were not comparable due to differences in ingredients and population imbalance and, therefore, an unanchored matching-adjusted indirect comparison (MAIC) was used, which reweighted IPD for crisaborole to estimate absolute response in comparator populations.ResultsThe odds of achieving an improvement in ISGA score was higher with crisaborole 2% versus pimecrolimus 1% (odds ratio [OR] 2.03; 95% confidence interval [CI] 1.45–2.85; effective sample size = 627, reduced from 1021; p value < 0.001) and for crisaborole 2% versus tacrolimus 0.03% (OR 1.50; 95% CI 1.09–2.05; effective sample size = 311, reduced from 1021; p = 0.012).ConclusionThe unanchored MAIC suggests that the odds of achieving an improvement in ISGA score is greater with crisaborole 2% than with pimecrolimus 1% or tacrolimus 0.03% in patients aged ≥ 2 years with mild-to-moderate AD. These results are consistent with findings from the previously published network meta-analysis, which used a different methodology for performing indirect treatment comparisons.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00646-1.

Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1β Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation.

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet’s disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1β were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-β1 pathway: therapeutic role of roflumilast

Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD) may be both a consequence and a cause of hypertension. Recent studies have demonstrated that phosphodiesterase 4 (PDE4)-cAMP signaling represents a pathway relevant to the pathophysiology of metabolic disorders. This study aims to investigate the impact and the underlying mechanism of PDE4 in the pathogenesis of NAFLD and its associated hypertension. Here we demonstrated that high-fat-diet (HFD) fed mice developed NAFLD and hypertension, with an associated increase in hepatic PDE4D expression, which can be prevented and even reversed by PDE4 inhibitor roflumilast. Furthermore, we demonstrated that hepatic overexpression of PDE4D drove significant hepatic steatosis and elevation of blood pressure. Mechanistically, PDE4D activated fatty acid translocase CD36 signaling which facilitates hepatic lipid deposition, resulting in TGF-β1 production by hepatocytes and excessive TGF-β1 signaling in vessels and consequent hypertension. Specific silencing of TGF-β1 in hepatocytes by siRNA using poly (β-amino ester) nanoparticles significantly normalized hepatic PDE4D overexpression-activated TGF-β1 signaling in vessels and hypertension. Together, the conclusions indicated that PDE4D plays an important role in the pathogenesis of NAFLD and associated hypertension via activation of CD36-TGF-β1 signaling in the liver. PDE4 inhibitor such as roflumilast, which is clinically approved for chronic obstructive pulmonary disease (COPD) treatment, has the potential to be used as a preventive or therapeutic drug against NAFLD and associated hypertension in the future.

Tanimilast, A Novel Inhaled Pde4 Inhibitor for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease.

Chronic respiratory diseases are the third leading cause of death, behind cardiovascular diseases and cancer, affecting approximately 550 million of people all over the world. Most of the chronic respiratory diseases are attributable to asthma and chronic obstructive pulmonary disease (COPD) with this latter being the major cause of deaths. Despite differences in etiology and symptoms, a common feature of asthma and COPD is an underlying degree of airways inflammation. The nature and severity of this inflammation might differ between and within different respiratory conditions and pharmacological anti-inflammatory treatments are unlikely to be effective in all patients. A precision medicine approach is needed to selectively target patients to increase the chance of therapeutic success. Inhibitors of the phosphodiesterase 4 (PDE4) enzyme like the oral PDE4 inhibitor roflumilast have shown a potential to reduce inflammatory-mediated processes and the frequency of exacerbations in certain groups of COPD patients with a chronic bronchitis phenotype. However, roflumilast use is dampened by class related side effects as nausea, diarrhea, weight loss and abdominal pain, resulting in both substantial treatment discontinuation in clinical practice and withdrawal from clinical trials. This has prompted the search for PDE4 inhibitors to be given by inhalation to reduce the systemic exposure (and thus optimize the systemic safety) and maximize the therapeutic effect in the lung. Tanimilast (international non-proprietary name of CHF6001) is a novel highly potent and selective inhaled PDE4 inhibitor with proven anti-inflammatory properties in various inflammatory cells, including leukocytes derived from asthma and COPD patients, as well as in experimental rodent models of pulmonary inflammation. Inhaled tanimilast has reached phase III clinical development by showing promising pharmacodynamic results associated with a good tolerability and safety profile, with no evidence of PDE4 inhibitors class-related side effects. In this review we will discuss the main outcomes of preclinical and clinical studies conducted during tanimilast development, with particular emphasis on the characterization of the pharmacodynamic profile that led to the identification of target populations with increased therapeutic potential in inflammatory respiratory diseases.

Apremilast effectively inhibits TNFα-induced vascular inflammation in human endothelial cells.

Patients with chronic inflammatory diseases (e.g. psoriasis and rheumatoid arthritis) are at increased risk for the development of atherosclerosis and cardiovascular diseases (CVD). Previous studies have suggested that phosphodiesterase 4 (PDE4) inhibitors possess anti-inflammatory properties. Here we examined the effect of the PDE4 inhibitor apremilast, a well-established anti-psoriatic drug, on pro-inflammatory responses in TNFα-activated endothelial cells. Human umbilical vein endothelial cells (HUVEC) were treated with tumour necrosis factor-α (TNFα) in the presence or absence of apremilast. Expression levels of pro-inflammatory cytokines, chemokines and adhesion molecules were assessed by ELISA, western blot and RT-PCR. Effects of apremilast on adhesion and transendothelial migration (TEM) of THP-1 monocytic cells were analysed in transwell assays. Apremilast suppressed TNFα-induced expression and secretion of important endothelial and monocytic pro-inflammatory factors, including granulocyte-macrophage colony-stimulating factor (GM-CSF), C-X-C motif chemokine ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), vascular cell adhesion molecule 1 (VCAM-1), E-selectin and matrix metalloproteinase-9 (MMP9). Functionally, apremilast reduced adhesion of THP-1 cells to activated HUVECs and TEM in response to TNFα. Mechanistically, apremilast suppressed activation of nuclear factor κB (NFκB) and mitogen-activated protein kinases (MAPK) signalling in activated HUVECs. Furthermore, inhibition of p38, C-Jun-N-terminale Kinase (JNK) and NFκB in activated HUVECs decreased expression of GM-CSF, VCAM-1 and E-selectin. Additionally, apremilast decreased IL-17A-induced secretion of IL-6 and CCL2. We demonstrate that apremilast has distinct anti-inflammatory effects in activated HUVECs, indicating that apremilast could have the therapeutic potential to prevent higher risk for CVD in patients with chronic inflammatory diseases.

Lattice water provides hydrogen atom donor to form hydrate: A case study of chlorbipram: m-hydroxybenzoic acid (1:1) cocrystal

Cocrystal hydrate accounts for a small percentage of cocrystals of poorly water-soluble drugs, and still lack the explanation on its cause of formation. In this study, a cocrystal hydrate with a novel phosphodiesterase-4 (PDE-4) inhibitor, chlorbipram, is prepared and characterized using multi-techniques. The dissolution behavior, ternary phase diagram and theoretical calculations are further performed and discussed. Chlorbipram: m-Hydroxybenzoic acid (ChBP-MHBA, 1: 1) cocrystal hydrate presents approximate equivalent dissolution (1.61 mg/mL) in comparison with ChBP (1.90 mg/mL) in isopropanol/water (1: 1, v/v) solution. Ternary phase diagram plotted in ethyl acetate solvent suggests that ChBP-MHBA cocrystal hydrate has an optimum mass percentage range from (2.91%: 2.64%: 94.45%) to (3.20%: 10.74%: 86.06%) among ChBP, MHBA and ethyl acetate. There are two lattice waters in each unit cell of ChBP-MHBA cocrystal hydrate, accounting for 4.5% proportion of the cell volume using contact surface calculations. Molecular Electrostatic Potential Surface (MEPS) investigations indicate that the strong hydrogen bonds are formed within the cocrystal lattice, which are between the global minimum values of ChBP/MHBA and the global maximum values of lattice water. In summary, lattice water plays an important role in the formation of cocrystal hydrate, providing hydrogen atom donor and forming hydrogen bonds to support its three-dimensional crystal structure.

A Large Multicenter Real-World Evidence (RWE) Analysis of Autoimmune (AI) Diseases and Lymphoma: Histologic Associations, Disease Characteristics, Survival, and Prognostication

A Large Multicenter Real-World Evidence (RWE) Analysis of Autoimmune (AI) Diseases and Lymphoma: Histologic Associations, Disease Characteristics, Survival, and Prognostication

Treatment with IMR-687, a Highly Selective PDE9 Inhibitor, Increases HbF and Reduces VOCs in Adults with Sickle Cell Disease in a Long-Term, Phase 2a, Open-Label Extension Study

IntroductionIMR-687 (tovinontrine) is a highly selective phosphodiesterase 9 (PDE9) inhibitor being developed as an orally administered therapy for patients with sickle cell disease (SCD) and beta-thalassemia. IMR-687 increases intracellular cGMP levels and has been shown in preclinical studies to increase fetal hemoglobin (HbF) expression and reduce hemolysis and sickling of RBCs, which can lead to painful vaso-occlusive crisis (VOC). In a Phase 2a, randomized, double-blind, placebo-controlled study of adult patients with SCD (N=93) (NCT03401112), IMR-687 was generally well-tolerated as a monotherapy and in combination with hydroxyurea (HU) (European Hematology Association Annual Congress 2021, Abstract S263). IMR-687 treatment with 50-200 mg once daily (N=63) for up to 6 months, as compared with placebo (N=30), resulted in a 40% lower mean annualized rate of VOCs, 38% lower mean annualized rate of VOC-related hospitalizations, and increased median time to first VOC (169 days vs 87 days, respectively, p=0.029). Improvements were also observed in patient-reported outcomes regarding pain episode severity (ASCQ-Me) and percentage of RBCs containing HbF (F-cells).MethodsA Phase 2a open-label extension (OLE) study (NCT04053803) is ongoing to assess the long-term safety and benefit of IMR-687 administered to adult subjects with SCD for up to 4 years. Secondary long-term pharmacokinetic (PK) and pharmacodynamic (PD) parameters are also being examined. The use of background HU is permitted. The Safety Review Committee meets regularly and ad hoc as necessary.Subjects were eligible upon completion of the Phase 2a parent study (16 or 24 weeks depending on the assigned treatment arm and without early withdrawal) and if they met all inclusion and exclusion criteria. For subjects without treatment interruption, baseline values from the parent study were used, as appropriate. The dose of IMR-687 initially administered in the OLE study was 200 mg as a once daily oral dose. The dose of IMR-687 is planned to be increased to 300 or 400 mg daily, depending on the subject's weight.Subjects are evaluated every 4-6 months for safety, PK and PD parameters (including HbF, F-cells, hemoglobin [Hb] and other biomarkers) as well as incidence of VOCs.ResultsAs of a data cut-off of 12-May-2021, 24 subjects were enrolled in the OLE study, 17 of which had a treatment interruption between the parent and OLE studies, and 7 subjects had direct roll-over to the OLE study. Seventeen of the OLE subjects were treated with IMR-687 monotherapy and 7 subjects were treated with combination IMR-687 + HU.IMR-687 continued to be well-tolerated in the OLE study (N=24). There were no treatment-related serious adverse events (SAEs), and the most common (≥10%) AEs were headache (21% of subjects), back pain (17%) and nausea (13%). There were 3 (13%) subjects with VOC-related hospitalizations.Annualized VOC rate was analyzed for 18 subjects treated for at least 200 days in the OLE study. Subjects who were previously in the active treatment arm in the parent study (N=13) maintained a low mean annualized VOC rate while continuing IMR-687 in the OLE study (1.35/yr [parent] and 1.85/yr [OLE]); subjects previously treated with placebo (N=5) had a 39% reduction in VOC rate when switched to IMR-687 (4.71/yr [parent] vs 2.89/yr [OLE]) (Figure 1). Of 15 subjects with evaluable PD data at 8 months, 7 (47%) subjects had a ≥ 6% absolute increase in F-cells, and 4 of 11 (36%) subjects had a ≥ 3% absolute increase in HbF (Figure 2). Updated data for subjects completing 12 months in the OLE study will be presented.ConclusionsConsistent with the parent study, preliminary results from the ongoing Phase 2a OLE study demonstrate that daily dosing of 200 mg IMR-687 was well-tolerated with longer-term treatment as a monotherapy or in combination with HU. IMR-687 treatment reduced the annualized rate of VOCs and increased HbF (%) and F-cells (%). Based on these encouraging data, a Phase 2b study (NCT04474314) is ongoing to further explore IMR-687 at doses up to 400 mg daily as a disease-modifying therapy for SCD. [Display omitted] DisclosuresBarysauskas: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Yen: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Tang: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Ballal: Imara Inc.: Current Employment, Current equity holder in publicly-traded company. Attie: Imara Inc.: Current Employment, Current equity holder in publicly-traded company.

Once-Daily Roflumilast Cream 0.3%, a Potent Phosphodiesterase-4 Inhibitor, Provided Safe and Effective Treatment of Psoriasis in the DERMIS-1 and DERMIS-2 Phase 3 Trials

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M312 CRISABOROLE FOR THE TREATMENT OF SEVERE CONTACT DERMATITIS UNRESPONSIVE TO CORTICOSTEROIDS

Contact dermatitis is a type IV hypersensitivity reaction. Treatment for contact dermatitis includes corticosteroids and the removal of the causal agent. Crisaborole is a phosphodiesterase-4 (PDE-4) inhibitor that is currently approved for mild-to-moderate eczema for 3 months of age and older. We present a case of contact dermatitis that was treated with crisaborole after being unresponsive to corticosteroids.

Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors.

Memory and cognitive functions depend on the cerebral levels of cyclic adenosine monophosphate (cAMP), which are regulated by the phosphodiesterase 4 (PDE4) family of enzymes. Selected rolipram-related PDE4 inhibitors, members of the GEBR library, have been shown to increase hippocampal cAMP levels, providing pro-cognitive benefits with a safe pharmacological profile. In a recent SAR investigation involving a subset of GEBR library compounds, we have demonstrated that, depending on length and flexibility, ligands can either adopt a twisted, an extended or a protruding conformation, the latter allowing the ligand to form stabilizing contacts with the regulatory domain of the enzyme. Here, based on those findings, we describe further chemical modifications of the protruding subset of GEBR library inhibitors and their effects on ligand conformation and potency. In particular, we demonstrate that the insertion of a methyl group in the flexible linker region connecting the catechol portion and the basic end of the molecules enhances the ability of the ligand to interact with both the catalytic and the regulatory domains of the enzyme.