Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: A propensity score matched retrospective cohort study in US veterans.

INTRODUCTION: Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long-term effects on the dementia/AD risk remain unknown. METHODS: A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health-care system from 2000 to 2020. RESULTS: A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52-0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long-term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39-0.83) during the 20 years of follow-up. CONCLUSION: TNF inhibitor use is associated with lower long-term risk of dementia/AD among US veterans with RA.

Effects of chronic inhibition of phosphodiesterase-4D on behavior and regional rates of cerebral protein synthesis in a mouse model of fragile X syndrome.

Fragile X Syndrome (FXS) is caused by silencing the FMR1 gene which results in intellectual disability, hyperactivity, sensory hypersensitivity, autistic-like behavior, and susceptibility to seizures. This X-linked disorder is also associated with reduced cAMP levels in humans as well as animal models. We assessed the therapeutic and neurochemical effects of chronic administration of the phosphodiesterase-4D negative allosteric modulator, BPN14770, in a mouse model of FXS (Fmr1 KO). Groups of male Fmr1 KO mice and control littermates were treated with dietary BPN14770 commencing postnatal day 21. A dose-response effect was investigated. At 90 days of age, mice underwent behavior tests including open field, novel object recognition, three chambered sociability and social novelty tests, passive avoidance, and sleep duration analysis. These tests were followed by in vivo measurement of regional rates of cerebral protein synthesis (rCPS) with the autoradiographic L-[1-14C]leucine method. BPN14770 treatment had positive effects on the behavioral phenotype in Fmr1 KO mice. Some effects such as increased sleep duration and increased social behavior occurred in both genotypes. In the open field, the hyperactivity response in Fmr1 KO mice was ameliorated by BPN14770 treatment at low and intermediate doses. BPN14770 treatment tended to increase rCPS in a dose-dependent manner in WT mice, whereas in Fmr1 KO mice effects on rCPS were less apparent. Results indicate BPN14770 treatment improves some behavior in Fmr1 KO mice. Results also suggest a genotype difference in the regulation of translation via a cAMP-dependent pathway.

COVID-19 and dementia: Analyses of risk, disparity, and outcomes from electronic health records in the US.

INTRODUCTION: At present, there is limited data on the risks, disparity, and outcomes for COVID-19 in patients with dementia in the United States. METHODS: This is a retrospective case-control analysis of patient electronic health records (EHRs) of 61.9 million adult and senior patients (age ≥ 18 years) in the United States up to August 21, 2020. RESULTS: Patients with dementia were at increased risk for COVID-19 compared to patients without dementia (adjusted odds ratio [AOR]: 2.00 [95% confidence interval (CI), 1.94-2.06], P < .001), with the strongest effect for vascular dementia (AOR: 3.17 [95% CI, 2.97-3.37], P < .001), followed by presenile dementia (AOR: 2.62 [95% CI, 2.28-3.00], P < .001), Alzheimer's disease (AOR: 1.86 [95% CI, 1.77-1.96], P < .001), senile dementia (AOR: 1.99 [95% CI, 1.86-2.13], P < .001) and post-traumatic dementia (AOR: 1.67 [95% CI, 1.51-1.86] P < .001). Blacks with dementia had higher risk of COVID-19 than Whites (AOR: 2.86 [95% CI, 2.67-3.06], P < .001). The 6-month mortality and hospitalization risks in patients with dementia and COVID-19 were 20.99% and 59.26%, respectively. DISCUSSION: These findings highlight the need to protect patients with dementia as part of the strategy to control the COVID-19 pandemic.

Protection from Amyloid ß Peptide-Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor.

Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aß 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aß impairment. Microinjection of oligomeric Aß 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aß-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aß-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT: This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aß 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Aß 1-42 neurotoxicity.

A negative allosteric modulator of PDE4D enhances learning after traumatic brain injury.

Traumatic brain injury (TBI) significantly decreases cyclic AMP (cAMP) signaling which produces long-term synaptic plasticity deficits and chronic learning and memory impairments. Phosphodiesterase 4 (PDE4) is a major family of cAMP hydrolyzing enzymes in the brain and of the four PDE4 subtypes, PDE4D in particular has been found to be involved in memory formation. Although most PDE4 inhibitors target all PDE4 subtypes, PDE4D can be targeted with a selective, negative allosteric modulator, D159687. In this study, we hypothesized that treating animals with D159687 could reverse the cognitive deficits caused by TBI. To test this hypothesis, adult male Sprague Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. After 3 months of recovery, animals were treated with D159687 (0.3 mg/kg, intraperitoneally) at 30 min prior to cue and contextual fear conditioning, acquisition in the water maze or during a spatial working memory task. Treatment with D159687 had no significant effect on these behavioral tasks in non-injured, sham animals, but did reverse the learning and memory deficits in chronic TBI animals. Assessment of hippocampal slices at 3 months post-TBI revealed that D159687 reversed both the depression in basal synaptic transmission in area CA1 as well as the late-phase of long-term potentiation. These results demonstrate that a negative allosteric modulator of PDE4D may be a potential therapeutic to improve chronic cognitive dysfunction following TBI.

Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor.

UNLABELLED: Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI. SIGNIFICANCE STATEMENT: Currently, there are an estimated 3.2-5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of 10 of these individuals report cognitive disabilities (Thurman et al., 1999; Lew et al., 2006; Zaloshnja et al., 2008). One of the molecular mechanisms associated with chronic cognitive disabilities is impaired cAMP signaling in the hippocampus. In this study, we report that a selective phosphodiesterase 4B (PDE4B) inhibitor reduces chronic cognitive deficits after TBI and rescues deficits in hippocampal long-term potentiation. These results suggest that PDE4B inhibition has the potential to improve learning and memory ability and overall functioning for people living with TBI.

Discovery of triazines as selective PDE4B versus PDE4D inhibitors.

In this study we report a series of triazine derivatives that are potent inhibitors of PDE4B. We also provide a series of structure activity relationships that demonstrate the triazine core can be used to generate subtype selective inhibitors of PDE4B versus PDE4D. A high resolution co-crystal structure shows that the inhibitors interact with a C-terminal regulatory helix (CR3) locking the enzyme in an inactive 'closed' conformation. The results show that the compounds interact with both catalytic domain and CR3 residues. This provides the first structure-based approach to engineer PDE4B-selective inhibitors.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome.

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.

We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.

Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA), one of the most common genetic causes of infant death, results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of survival motor neuron (SMN) protein. In humans, the SMN gene is duplicated; SMA results from the loss of SMN1 but SMN2 remains intact. SMA severity is related to the copy number of SMN2. Compounds which increase the expression of SMN2 could, therefore, be potential therapeutics for SMA. Ultrahigh-throughput screening recently identified substituted quinazolines as potent SMN2 inducers. A series of C5-quinazoline derivatives were tested for their ability to increase SMN expression in vivo. Oral administration of three compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. We then examined the effect of these compounds on the progression of disease in SMN lacking exon 7 (SMNDelta7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 21-30% when given prior to motor neuron loss. In summary, the C5-quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11 and ameliorates the motor phenotype of SMNDelta7 SMA mice.

Small molecule allosteric modulators of phosphodiesterase 4.

Phosphodiesterase 4 (PDE4) inhibitors have shown benefit in human clinical trials but dosing is limited by tolerability, particularly because of emesis. Novel cocrystal structures of PDE4 catalytic units with their regulatory domains together with bound inhibitors have revealed three different PDE4 conformers that can be exploited in the design of novel therapeutic agents. The first is an open conformer, which has been employed in the traditional approach to the design of competitive PDE4 inhibitors. The second is an asymmetric dimer in which a UCR2 regulatory helix from one monomer is placed in a closed conformation over the opposite active site in the PDE4 dimer (trans-capping). Only one active site can be closed by an inhibitor at a time with the consequence that compounds exploiting this conformer only partially inhibit PDE4 enzymatic activity while retaining potency in cellular and in vivo models. By placing an intrinsic ceiling on the magnitude of PDE4 inhibition, such compounds may better maintain spatial and temporal patterning of signaling in cAMP microdomains with consequent improved tolerability. The third is a symmetric PDE4 conformer in which helices from the C-terminal portion of the catalytic unit cap both active sites (cis-capping). We propose that dual-gating of PDE4 activity may be further fine tuned by accessory proteins that recognize open or closed conformers of PDE4 regulatory helices.

Gut-microbiota-microglia-brain interactions in Alzheimer's disease: knowledge-based, multi-dimensional characterization.

BACKGROUND: Interactions between the gut microbiota, microglia, and aging may modulate Alzheimer's disease (AD) pathogenesis but the precise nature of such interactions is not known. METHODS: We developed an integrated multi-dimensional, knowledge-driven, systems approach to identify interactions among microbial metabolites, microglia, and AD. Publicly available datasets were repurposed to create a multi-dimensional knowledge-driven pipeline consisting of an integrated network of microbial metabolite-gene-pathway-phenotype (MGPPN) consisting of 34,509 nodes (216 microbial metabolites, 22,982 genes, 1329 pathways, 9982 mouse phenotypes) and 1,032,942 edges. RESULTS: We evaluated the network-based ranking algorithm by showing that abnormal microglia function and physiology are significantly associated with AD pathology at both genetic and phenotypic levels: AD risk genes were ranked at the top 6.4% among 22,982 genes, P < 0.001. AD phenotypes were ranked at the top 11.5% among 9982 phenotypes, P < 0.001. A total of 8094 microglia-microbial metabolite-gene-pathway-phenotype-AD interactions were identified for top-ranked AD-associated microbial metabolites. Short-chain fatty acids (SCFAs) were ranked at the top among prioritized AD-associated microbial metabolites. Through data-driven analyses, we provided evidence that SCFAs are involved in microglia-mediated gut-microbiota-brain interactions in AD at both genetic, functional, and phenotypic levels. CONCLUSION: Our analysis produces a novel framework to offer insights into the mechanistic links between gut microbial metabolites, microglia, and AD, with the overall goal to facilitate disease mechanism understanding, therapeutic target identification, and designing confirmatory experimental studies.

Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

Tumor Necrosis Factor (TNF) blocking agents are associated with lower risk for Alzheimer's disease in patients with rheumatoid arthritis and psoriasis.

This large, retrospective case-control study of electronic health records from 56 million unique adult patients examined whether or not treatment with a Tumor Necrosis Factor (TNF) blocking agent is associated with lower risk for Alzheimer's disease (AD) in patients with rheumatoid arthritis (RA), psoriasis, and other inflammatory diseases which are mediated in part by TNF and for which a TNF blocker is an approved treatment. The analysis compared the diagnosis of AD as an outcome measure in patients receiving at least one prescription for a TNF blocking agent (etanercept, adalimumab, and infliximab) or for methotrexate. Adjusted odds ratios (AORs) were estimated using the Cochran-Mantel-Haenszel (CMH) method and presented with 95% confidence intervals (CIs) and p-values. RA was associated with a higher risk for AD (Adjusted Odds Ratio (AOR) = 2.06, 95% Confidence Interval: (2.02-2.10), P-value <0.0001) as did psoriasis (AOR = 1.37 (1.31-1.42), P <0.0001), ankylosing spondylitis (AOR = 1.57 (1.39-1.77), P <0.0001), inflammatory bowel disease (AOR = 2.46 (2.33-2.59), P < 0.0001), ulcerative colitis (AOR = 1.82 (1.74-1.91), P <0.0001), and Crohn's disease (AOR = 2.33 (2.22-2.43), P <0.0001). The risk for AD in patients with RA was lower among patients treated with etanercept (AOR = 0.34 (0.25-0.47), P <0.0001), adalimumab (AOR = 0.28 (0.19-0.39), P < 0.0001), or infliximab (AOR = 0.52 (0.39-0.69), P <0.0001). Methotrexate was also associated with a lower risk for AD (AOR = 0.64 (0.61-0.68), P <0.0001), while lower risk was found in patients with a prescription history for both a TNF blocker and methotrexate. Etanercept and adalimumab also were associated with lower risk for AD in patients with psoriasis: AOR = 0.47 (0.30-0.73 and 0.41 (0.20-0.76), respectively. There was no effect of gender or race, while younger patients showed greater benefit from a TNF blocker than did older patients. This study identifies a subset of patients in whom systemic inflammation contributes to risk for AD through a pathological mechanism involving TNF and who therefore may benefit from treatment with a TNF blocking agent.

PDE4 subtypes in cancer.

Cyclic nucleotide phosphodiesterases (PDE) break down cyclic nucleotides such as cAMP and cGMP, reducing the signaling of these important intracellular second messengers. Several unique families of phosphodiesterases exist, and certain families are clinically important modulators of vasodilation. In the current work, we have summarized the body of literature that describes an emerging role for the PDE4 subfamily of phosphodiesterases in malignancy. We have systematically investigated PDE4A, PDE4B, PDE4C, and PDE4D isoforms and found evidence associating them with several cancer types including hematologic malignancies and lung cancers, among others. In this review, we compare the evidence examining the functional role of each PDE4 subtype across malignancies, looking for common signaling themes, signaling pathways, and establishing the case for PDE4 subtypes as a potential therapeutic target for cancer treatment.

A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt/Bcl-2 Pathway.

A global, quantitative proteomics/systems-biology analysis of the selective pharmacological inhibition of phosphodiesterase-4D (PDE4D) revealed the differential regulation of pathways associated with neuroplasticity in memory-associated brain regions. Subtype selective inhibitors of PDE4D bind in an allosteric site that differs between mice and humans in a single amino acid (tyrosine vs. phenylalanine, respectively). Therefore to study selective inhibition of PDE4D by BPN14770, a subtype selective allosteric inhibitor of PDE4D, we utilized a line of mice in which the PDE4D gene had been humanized by mutating the critical tyrosine to phenylalanine. Relatively low doses of BPN14770 were effective at reversing scopolamine-induced memory and cognitive deficits in humanized PDE4D mice. Inhibition of PDE4D alters the expression of protein kinase A (PKA), Sirt1, Akt, and Bcl-2/Bax which are components of signaling pathways for regulating endocrine response, stress resistance, neuronal autophagy, and apoptosis. Treatment with a series of antagonists, such as H89, sirtinol, and MK-2206, reversed the effect of BPN14770 as shown by behavioral tests and immunoblot analysis. These findings suggest that inhibition of PDE4D enhances signaling through the cAMP-PKA-SIRT1-Akt -Bcl-2/Bax pathway and thereby may provide therapeutic benefit in neurocognitive disorders.

Discovery, Radiolabeling, and Evaluation of Subtype-Selective Inhibitors for Positron Emission Tomography Imaging of Brain Phosphodiesterase-4D.

We aimed to develop radioligands for PET imaging of brain phosphodiesterase subtype 4D (PDE4D), a potential target for developing cognition enhancing or antidepressive drugs. Exploration of several chemical series gave four leads with high PDE4D inhibitory potency and selectivity, optimal lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl cores. They were successfully labeled with carbon-11 (t1/2 = 20.4 min) for evaluation with PET in monkey. Whereas two of these radioligands did not provide PDE4D-specific signal in monkey brain, two others, [11C]T1660 and [11C]T1650, provided sizable specific signal, as judged by pharmacological challenge using rolipram or a selective PDE4D inhibitor (BPN14770) and subsequent biomathematical analysis. Specific binding was highest in prefrontal cortex, temporal cortex, and hippocampus, regions that are important for cognitive function. [11C]T1650 was progressed to evaluation in humans with PET, but the output measure of brain enzyme density (VT) increased with scan duration. This instability over time suggests that radiometabolite(s) were accumulating in the brain. BPN14770 blocked PDE4D uptake in human brain after a single dose, but the percentage occupancy was difficult to estimate because of the unreliability of measuring VT. Overall, these results show that imaging of PDE4D in primate brain is feasible but that further radioligand refinement is needed, most likely to avoid problematic radiometabolites.

Heterocyclic 1,7-disubstituted indole sulfonamides are potent and selective human EP3 receptor antagonists.

We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP(3) receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels.

3-Acrylamide-4-aryloxyindoles: synthesis, biological evaluation and metabolic stability of potent and selective EP3 receptor antagonists.

A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.

Peri-substituted hexahydro-indolones as novel, potent and selective human EP3 receptor antagonists.

A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP(3) receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE(2) and fits into an internally generated EP(3) pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.