pyrimidinones and Cognition-Disorders

PF-04447943 is a potent, selective phosphodiesterase 9A (PDE9A) inhibitor that elevates guanoscine 3',5' - cyclic monophosphate (cGMP) in brain and cerebrospinal fluid. PDE9A inhibition enhances synaptic plasticity and improves memory in preclinical cognition models, and prevents decreases in dendritic spine density in transgenic mice that overexpress amyloid precursor protein (APP) leading to high levels of amyloid beta (Aβ) production (Tg2576).. This Phase 2 multicenter study was designed to assess the efficacy, safety and pharmacokinetics of PF-04447943 compared with placebo in mild to moderate probable Alzheimer's disease (AD).. Subjects in overall good health with Mini Mental State Examination (MMSE) scores of 14-26 were randomized to 12 weeks treatment with PF-04447943 25 mg q12h (n=91) or placebo (n=100). Concomitant acetylcholinesterase inhibitor or memantine use was excluded. The primary outcome was the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog). The Neuropsychiatric Inventory (NPI), Clinical Global Impression-Improvement scale (CGI-I) and standard safety measures were secondary outcomes.. Completion rates were similar, 87% PF-04447943 vs 92% placebo. At week 12 the mean (SE) baseline adjusted decrease from baseline in ADAS cog for PF-04447943-treated patients was -1.91 (0.54). Placebo treated patients had a change of -1.60 (0.50). The difference between treatments was -0.31 (90% CI of -1.52, 0.90). Corresponding values for the NPI were -2.86 (0.72) vs -2.70 (0.67) with a treatment difference of -0.16 (90% CI of -1.78, 1.48). Neither these changes nor the distribution of CGI-I scores were statistically significantly different between groups. The incidence of serious adverse events (AEs) was similar between groups with 2 deaths in the placebo group. The PF-04447943 group reported more gastrointestinal AEs including diarrhea (5.5% vs 3%) and nausea (5.5% vs 1%) and had a higher rate of discontinuation due to AEs (6.6% vs 2%).. Although generally safe and well-tolerated, 12 weeks PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Double-Blind Method; Female; Humans; Male; Mental Status Schedule; Middle Aged; Neuropsychological Tests; Outcome Assessment, Health Care; Phosphodiesterase Inhibitors; Pyrazoles; Pyrimidinones; Treatment Outcome

Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent and caspase-independent cell apoptosis. It has been verified that Omi/HtrA2 is related to apoptosis due to oxidative stress, which may play an important role in the integrity of mitochondria. Ucf-101 is a specific inhibitor of Omi/HtrA2 and it has been demonstrated that Ucf-101 has organ protective effects in a variety of in vitro and in vivo studies. The aim of our study was to examine the neuroprotective effects of Ucf-101 on cerebral oxidative injury and cognitive impairment in septic rats.. Male Sprague Dawley rats are subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy. Rats were divided into 4 groups: (1) a sham group plus normal saline (10 mL/kg); (2) a sham group plus Ucf-101 (10 umol/kg); (3) CLP plus normal saline (10 mL/kg); and (4) CLP plus Ucf-101 (10 umol/kg). Brain tumor necrosis factor (TNF)-α level, caspase-3 and caspase-9 activities, malondialdehyde (MDA) content and catalase (CAT) activities were examined. TUNEL staining was utilized to evaluate the amount of apoptosis and the cognitive function was evaluated by the MWM test. The study also assessed the clinical scores of animals and the survival time for the 7-day period.. CLP resulted in a poor survival rate, evidence of hippocampal oxidative injury, cell apoptosis and cognitive dysfunction as well as elevated TNF-α level and caspases activities, increased weight loss and clinical scores. Ucf-101 pre-treatment could significantly inhibit caspases activities and cell apoptosis, reduce TNF-α and MDA levels, slightly reverse CAT activities in the brain and attenuate this CLP effect on cognitive dysfunction. In addition, the survival rate and survival time was significantly improved by pre-treatment with Ucf-101.. The present results demonstrated that ucf-101 has the neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats.

Topics: Animals; Apoptosis; Brain Diseases; Caspase 3; Caspase 9; Cognition Disorders; Lipid Peroxidation; Male; Malondialdehyde; Neuroprotective Agents; Oxidative Stress; Pyrimidinones; Rats; Rats, Sprague-Dawley; Sepsis; Thiones; Tumor Necrosis Factor-alpha

6-[(3S,4S)-4-Methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943) is a novel PDE9A inhibitor identified using parallel synthetic chemistry and structure-based drug design (SBDD) and has advanced into clinical trials. Selectivity for PDE9A over other PDE family members was achieved by targeting key residue differences between the PDE9A and PDE1C catalytic site. The physicochemical properties of the series were optimized to provide excellent in vitro and in vivo pharmacokinetics properties in multiple species including humans. It has been reported to elevate central cGMP levels in the brain and CSF of rodents. In addition, it exhibits procognitive activity in several rodent models and synaptic stabilization in an amyloid precursor protein (APP) transgenic mouse model. Recent disclosures from clinical trials confirm that it is well tolerated in humans and elevates cGMP in cerebral spinal fluid of healthy volunteers, confirming that it is a quality pharmacological tool for testing clinical hypotheses in disease states associated with impairment of cGMP signaling or cognition.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Amyloid beta-Protein Precursor; Animals; Brain; Catalytic Domain; Cognition Disorders; Crystallography, X-Ray; Cyclic GMP; Dogs; Drug Design; Hippocampus; Humans; Long-Term Potentiation; Maze Learning; Mice; Mice, Transgenic; Microsomes, Liver; Models, Molecular; Protein Conformation; Pyrazoles; Pyrimidinones; Rats; Stereoisomerism; Structure-Activity Relationship; Synapses

Numerous changes occur during aging and Alzheimer's disease (AD) progression, including a decline in cholinergic functioning and cognition, as well as alterations in gene expression and activity in the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway. Donepezil, the current standard of care for Alzheimer's disease, improves cholinergic functioning and has demonstrated effects on multiple domains of cognition, including memory and attention in both preclinical species and patients. We previously found that increasing activation of the NO/cGMP pathway via phosphodiesterase 9 (PDE9) inhibition also improves memory in rodents and suggested that PDE9 might be a promising target for novel treatments for AD. Here we investigated whether PDE9 inhibition also enhances attention using a novel attention task in rats. We validated this task using several pharmacological manipulations and showed that the selective PDE9 inhibitor PF-04447943 produced effects similar to those of donepezil. These data confirm and extend the hypothesis that PDE9 inhibition might serve as a novel treatment for AD and age-related cognitive decline.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cognition Disorders; Disease Models, Animal; Male; Nootropic Agents; Phosphodiesterase Inhibitors; Pyrazoles; Pyrimidinones; Rats; Rats, Wistar; Scopolamine

Valproic acid (VPA) has the potential to benefit patients suffering from human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine if VPA affects the plasma concentration of efavirenz (EFV) or lopinavir. HIV type 1 (HIV-1)-infected patients receiving EFV or lopinavir-ritonavir (LPV/r) had 9 or 10 blood samples drawn over 8 to 24 h of a dosing interval at steady state before and after receiving 250 mg of VPA twice daily for 7 days. VPA blood samples drawn before (C(0)) and 8 h after the morning dose (8 h) were compared to blood samples from a group of HIV-1-infected subjects who were taking either combined nucleoside reverse transcriptase inhibitors alone or had discontinued antiretroviral therapy. Pharmacokinetic parameters were calculated by noncompartmental analysis, and tests of bioequivalence were based on 90% confidence intervals (CIs) for ratios or differences. The geometric mean ratio (GMR) (90% CI) of the areas under the concentration-time curve from 0 to 24 h (AUC(0-24)s) of EFV (n = 11) with and without VPA was 1.00 (0.85, 1.17). The GMR (90% CI) of the AUC(0-8)s of LPV (n = 8) with and without VPA was 1.38 (0.98, 1.94). The differences (90% CI) in mean C(0) and 8-h VPA concentrations versus the control (n = 11) were -1.0 (-9.4, 7.4) microg/ml and -2.1 (-11.1, 6.9) microg/ml for EFV (n = 10) and -5.0 (-13.2, 3.3) microg/ml and -6.7 (-17.6, 4.2) microg/ml for LPV/r (n = 11), respectively. EFV administration alone is bioequivalent to EFV and VPA coadministration. LPV concentrations tended to be higher when the drug was combined with VPA. Results of VPA comparisons fail to raise concern that coadministration with EFV or LPV/r will significantly influence trough concentrations of VPA.

Topics: Adult; Alkynes; Anti-HIV Agents; Anticonvulsants; Area Under Curve; Benzoxazines; Cognition Disorders; Cyclopropanes; Drug Interactions; Female; Half-Life; HIV Infections; Humans; Lopinavir; Male; Oxazines; Pyrimidinones; Reverse Transcriptase Inhibitors; Valproic Acid