bay-73-6691 and Disease-Models--Animal

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Administration, Oral; Animals; Binding Sites; Catalytic Domain; Dementia, Vascular; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Half-Life; Humans; Maze Learning; Mice; Molecular Docking Simulation; Phosphodiesterase Inhibitors; Protein Isoforms; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Alzheimer's disease (AD) is accompanied by enhanced oxidative stress and excess free radicals. Phosphodiesterase 9 inhibitors (PDE-9Is) showed memory improving effects in many pharmacological deficit models. However, whether BAY 73-6691 (a selective PDE-9I) may attenuate the oxidative stress during the development of AD is still unclear. For this purpose, primary cultures of SH-SY5Y cells were incubated with 20μM beta-amyloid25-35 (Aβ25-35), followed by exposure to different concentrations (50, 100, 150 and 200μg/ml) of BAY 73-6691. Furthermore, the antioxidant effect of BAY 73-6691 was evaluated in mice subjected to intracerebroventricular injection of Aβ25-35 (day 0) and treatment with BAY 73-6691 by intraperitoneal injection once daily (days 1-10). Our results elucidated that treatment with BAY 73-6691 attenuated the Aβ25-35-induced cytotoxicity and oxidative stress in SH-SY5Y cells. In vivo, BAY 73-6691 protected Aβ25-35-induced oxidative damage in hippocampus, associated with the attenuation of impairments in hippocampal neurons. Administration of BAY 73-6691 improved learning and memory in the Morris water maze test, and restored several hippocampal memory-associated proteins. Our study identified a neuroprotective role for BAY 73-6691 against Aβ25-35-induced oxidative stress in vivo and in vitro, harboring therapeutic potential for the treatment of AD by alleviating the impairments in spatial memory and hippocampal neurons.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; Cell Line, Tumor; Disease Models, Animal; Hippocampus; Humans; In Vitro Techniques; Mice; Mice, Inbred ICR; Neurons; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Phosphodiesterase Inhibitors; Pyrazoles; Pyrimidines; Spatial Memory

Inhibition of leukocyte adhesion to the vascular endothelium represents a novel and important approach for decreasing sickle cell disease (SCD) vaso-occlusion. Using a humanized SCD-mouse-model of tumor necrosis factor-α-induced acute vaso-occlusion, we herein present data demonstrating that short-term administration of either hydroxyurea or the phosphodiesterase 9 (PDE9) inhibitor, BAY73-6691, significantly altered leukocyte recruitment to the microvasculature. Notably, the administration of both agents led to marked improvements in leukocyte rolling and adhesion and decreased heterotypic red blood cell-leukocyte interactions, coupled with prolonged animal survival. Mechanistically, these rheologic benefits were associated with decreased endothelial adhesion molecule expression, as well as diminished leukocyte Mac-1-integrin activation and cyclic guanosine monophosphate (cGMP)-signaling, leading to reduced leukocyte recruitment. Our findings indicate that hydroxyurea has immediate beneficial effects on the microvasculature in acute sickle-cell crises that are independent of the drug's fetal hemoglobin-elevating properties and probably involve the formation of intravascular nitric oxide. In addition, inhibition of PDE9, an enzyme highly expressed in hematopoietic cells, amplified the cGMP-elevating effects of hydroxyurea and may represent a promising and more tissue-specific adjuvant therapy for this disease.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Acute Disease; Anemia, Sickle Cell; Animals; Antisickling Agents; Cell Adhesion; Cell Communication; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Erythrocytes; Female; Humans; Hydroxyurea; Leukocyte Rolling; Leukocytes; Male; Mice; Mice, Inbred C57BL; Pyrazoles; Pyrimidines; Tumor Necrosis Factor-alpha; Vascular Diseases