PF-04447943 / Pfizer - LARVOL DELTA

PDE9A Inhibition Improves Coronary Microvascular Rarefaction and Left Ventricular Diastolic Dysfunction in the ZSF1 Rat Model of HFpEF. (PubMed, Microcirculation) - "Thus, in the ZSF1 rat model of human HFpEF, PDE9A inhibition improves coronary vascular rarefaction and LV diastolic dysfunction, demonstrating the usefulness of PDE9A inhibitors in ameliorating CMD and LV diastolic dysfunction through augmenting PRDX-dependent antioxidant mechanisms."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Genetic Disorders • Heart Failure • Hypertension • Metabolic Disorders • Obesity

Phosphodiesterase 9A inhibition improves aging-related increase in pulmonary vascular resistance in mice. (PubMed, Geroscience) - "Aged mice were treated with the selective PDE9A inhibitor PF04447943 (1 mg/kg/day) through intraperitoneal injections for 10 days...Additionally, changes in PVR were measured in response to perfusion of the endothelium-dependent agonist bradykinin or to nitric oxide (NO) donor sodium nitroprusside (SNP)...These data demonstrate a development of LV diastolic dysfunction and increase in PVR in aged mice. We propose that inhibitors of PDE9A could represent a novel therapeutic approach to specifically prevent aging-related pulmonary dysfunction."

Journal • Preclinical • Cardiovascular • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases

A systematic review on drugs for synaptic plasticity in the treatment of dementia. (PubMed, Ageing Res Rev) - "A total of 12 studies were selected on Levetiracetam, Masitinib, Saracatinib, BI 40930, Bryostatin 1, PF-04447943 and Edonerpic drugs. This could suggest that research on these drugs is still preliminary. Of all, three studies reported promising results on Levetiracetam, Bryostatin 1 and Masitinib."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

Combined ligand-based and structure-based design of PDE 9A inhibitors against Alzheimer's disease. (PubMed, Mol Divers) - "PF-04447943 and BI-409306 targeting PDE9 are undergoing clinical trials (Phase II). The hits were subjected to molecular dynamics (MD) studies, wherein they formed stable complexes with PDE9 protein and had ligand RMSDs within acceptable limits. The processes involved in the combined ligand and structure-based strategies."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Research progress of phosphodiesterase inhibitors in inflammatory bowel disease treatment. (PubMed, Zhejiang Da Xue Xue Bao Yi Xue Ban) - "In recent years, a series of researches suggest that PDE inhibitors such as several PDE4 inhibitors, PDE5 inhibitors (sildenafil, tadalafil and vardenafil), PDE3 inhibitors (cilostazol), PDE9 inhibitor (PF-04447943) and PDE3/PDE4 double inhibitor (pumafentrine) have ameliorating effect on experimental colitis in animals. In clinical trials, PDE4 inhibitor apremilast showed more therapeutic advantage than tetomilast. This article reviews the recent research progress of PDE inhibitors in treatment of inflammatory bowel disease."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization. (PubMed, Front Pharmacol) - "Therefore, we used female C57BL/6 mice treated with 3% DSS alone or co-treated with PF or sulfasalazine (SASP) to study the body weight, colon length, histopathology, and measure superoxide dismutase (SOD), malondialdehyde (MDA), and cGMP level, as well as cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-12/23 (IL-12/23), interleukin-10 (IL-10), and pathways including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and inflammasome activation. Importantly, PF reversed imbalance in Treg/T helper 17 cells (Th17) cells ratio, possibly by regulating dendritic cells and Treg developmental process. In summary, this study shows the protective effect of a PDE9A inhibitor in ulcerative colitis by suppressing oxidative stress and inflammation as well as reversing the Treg/Th17 cells imbalance."

Journal • Gastroenterology • Gastrointestinal Disorder • Genetic Disorders • Hematological Disorders • Immunology • Inflammation • Inflammatory Bowel Disease • Sickle Cell Disease • Stress Ulcer • Ulcerative Colitis • IL10 • IL12A • IL17A • IL6 • STAT3 • TNFA

Cyclic nucleotide signalling compartmentation by phosphodiesterases in cultured vascular smooth muscle cells. (PubMed, Br J Pharmacol) - "Our work underscores the distinct role of PDE1, PDE5 and PDE9 in locally regulating the [cAMP] and [cGMP] , in vascular smooth muscle cells, strengthening the concept of PDEs as key actors of cyclic nucleotide subcellular compartmentation."

Journal • Preclinical

Phosphodiesterase Inhibitors for Alzheimer's Disease: A Systematic Review of Clinical Trials and Epidemiology with a Mechanistic Rationale. (PubMed, J Alzheimers Dis Rep) - "Caffeine and cilostazol may lower AD risk. Denbufylline and sildenafil clinical trials are promising but preliminary and inconclusive. PF-04447943 and BI 409,306 are ineffective...Deprenyl/selegiline trials show only short-term benefits...Now, propentofylline is used to treat canine cognitive dysfunction, which, like AD, involves age-associated wild-type Aβ deposition. Phosphodiesterase inhibitors may prevent and treat AD."

Clinical • Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • BDNF • SIRT1

PF-04447943, a Phosphodiesterase 9A Inhibitor, in Stable Sickle Cell Disease Patients: A Phase Ib Randomized, Placebo-Controlled Study. (PubMed, Clin Transl Sci) - "This phase Ib study randomized patients with stable sickle cell disease (SCD) aged 18-65 years to twice-daily PF-04447943 (a phosphodiesterase 9A inhibitor; 5 or 25 mg) or placebo, with/without hydroxyurea coadministration, for up to 29 days. PF-04447943 demonstrated PK/PD effects suggestive of inhibiting pathways that may contribute to vaso-occlusion. This study also provides guidance regarding biomarkers for future SCD studies."

Biomarker • Clinical • Journal • P1 data • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Phosphodiesterase 9A Inhibition Facilitates Corticostriatal Transmission in Wild-Type and Transgenic Rats That Model Huntington's Disease. (PubMed, Front Neurosci) - "PDE9A inhibition also increased the proportion of MSNs responding to cortical stimulation and reversed deficits in spike probability observed in TG5 rats. As PDE9A is a cGMP specific enzyme, drugs such as PF-04447943 which act to facilitate striatal cGMP signaling and glutamatergic corticostriatal transmission could be useful therapeutic agents for restoring striatal function and alleviating motor and cognitive symptoms associated with HD."

Journal • Preclinical • Anesthesia • Huntington's Disease • Movement Disorders

Effect of phosphodiesterase (1B, 2A, 9A and 10A) inhibitors on central nervous system cyclic nucleotide levels of rats and mice. (PubMed, Neurochem Int) - "Male Sprague Dawley (Crl:CD [SD]) rats were dosed subcutaneously (sc) with a PDE1B inhibitor (DNS-0056), a PDE2A inhibitor (PF-05180999), a PDE9A inhibitor (PF-4447943), and a PDE10A inhibitor (MP10), each at a single dose of 10 or 30 mg/kg, or concomitantly with all 4 inhibitors at 10 mg/kg each...The drug exposures after concomitant treatment were also higher than in the individual inhibitor-treated animals. cGMP enhancement could be due to synergistic effects, though an additive effect of the combined inhibitor concentrations may also contribute."

Biomarker • Journal • Preclinical • CNS Disorders

The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 attenuates a scopolamine-induced deficit in a novel rodent attention task (Society of Biological Psychiatry,67th Annual Meeting) - Presentation time: Thursday, May 03 2012, 5:00 PM - 6:30 PM; PF-04447943 produced effects similar to those of donepezil, the current standard in care, when given at doses that only slightly elevated cGMP in rodent CSF (p<0.05 vs scopolamine; N=19-22/group)

Preclinical-animal • Alzheimer's Disease