fimasartan and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Inspired by the well-known PPARγ partial agonism of angiotensin II type 1 receptor (AT1R) antagonists exemplified by an antihypertensive drug, Telmisartan, efforts to identify compounds with the dual activities have been pursued in order to control the two major metabolic disorders, hypertension and hyperglycemia simultaneously. Lead compound 18 derived from the AT1R antagonist, Fimasartan, has successfully presented the possibility to control the medical conditions by a single molecule.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Area Under Curve; Biphenyl Compounds; Disease Models, Animal; Drug Discovery; Drug Partial Agonism; Half-Life; Hypoglycemic Agents; PPAR gamma; Proof of Concept Study; Pyrimidines; Structure-Activity Relationship; Tetrazoles

There is lack of researches on effects of intravenously injected mesenchymal stem cells (MSCs) against transient cerebral ischemia (TCI). We investigated the disruption of the neurovascular unit (NVU), which comprises the blood-brain barrier and examined entry of human dermis-derived MSCs (hDMSCs) into the damaged hippocampal CA1 area in a gerbil model of TCI and their subsequent effects on neuroprotection and cognitive function. Impairments of neurons and blood-brain barrier were examined by immunohistochemistry, electron microscopy, and Evans blue and immunoglobulin G leakage. Neuronal death was observed in pyramidal neurons 5-day postischemia. NVU were structurally damaged; in particular, astrocyte end-feet were severely damaged from 2-day post-TCI and immunoglobulin G leaked out of the CA1 area 2 days after 5 min of TCI; however, Evans blue extravasation was not observed. On the basis of the results of NVU damages, ischemic gerbils received PKH2-transfected hDMSCs 3 times at early times (3 hr, 2, and 5 days) after TCI, and fluorescence imaging was used to detect hDMSCs in the tissue. PKH2-transfected hDMSCs were not found in the CA1 from immediate time to 8 days after injection, although they were detected in the liver. Furthermore, hDMSCs transplantation did not protect CA1 pyramidal neurons and did not improve cognitive impairment. Intravenously transplanted hDMSCs did not migrate to the damaged CA1 area induced by TCI. These findings suggest no neuroprotection and cognitive improvement by intravenous hDMSCs transplantation after 5 min of TCI.

Topics: Animals; Biphenyl Compounds; Blood-Brain Barrier; Brain Ischemia; Dermis; Disease Models, Animal; Gerbillinae; Heterografts; Humans; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Pyramidal Cells; Pyrimidines; Tetrazoles

Nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which is composed of an NLRP3 domain, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) domain, and procaspase-1, plays an important role in the immune pathophysiology of the secondary damage induced by intracerebral hemorrhage (ICH). This study aims to investigate whether pre-stroke treatment with fimasartan, an angiotensin II receptor blocker, has anti-inflammatory effects on ICH by inhibiting the activation of the NLRP3 inflammasome. Sprague-Dawley rats were divided into five groups: sham, vehicle, low-dose (0.5 mg/kg) and regular-doses (1.0 and 3.0 mg/kg) fimasartan. These rats were treated for 30 days before the induction of collagenase-induced ICH and continuously 3 days after surgery. The mean blood pressure (BP) in the low-dose fimasartan group was not significantly different from that of control, and BP in the regular-dose groups was decreased in a dose-dependent manner. Pretreatment with low-dose fimasartan attenuated ICH-induced edema and improved neurological functions. Activation of the NLRP3/ASC/caspase-1 and the NF-κB pathways after ICH was markedly reduced by low-dose fimasartan. The double immunofluorescence staining of brain cells showed a significant decrease in the co-localization of NLRP3 with Iba1 (microglia marker) positive cells by fimasartan treatment. Cultured microglia cells stimulated by hemolysate demonstrated significant activation of the inflammasome, which was reduced by fimasartan. Pretreatment with a low-dose fimasartan alleviated brain damage after acute ICH by inhibiting the NLRP3 inflammasome without lowering MBP. Our study suggests pre-stroke administration of fimasartan could potentially attenuate ICH-induced secondary brain injury by targeting the inflammasome.

Topics: Animals; Biphenyl Compounds; Blood Pressure; Brain Edema; Brain Injuries; Calcium-Binding Proteins; Cells, Cultured; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Glial Fibrillary Acidic Protein; Male; Microfilament Proteins; Microglia; Neuroprotective Agents; NLR Family, Pyrin Domain-Containing 3 Protein; Pyrimidines; Rats; Rats, Sprague-Dawley; Tetrazoles; Vibrissae

Cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), was evaluated in a porcine model of acute myocardial infarction (MI). Fifty swine were randomized to group 1 (sham, n=10), group 2 (no angiotensin-converting enzyme inhibitor [ACEI] or ARB, n=10), group 3 (perindopril 2 mg daily, n=10), group 4 (valsartan 40 mg daily, n=10), or group 5 (fimasartan 30 mg daily, n=10). Acute MI was induced by occlusion of the left anterior descending artery for 50 min. Echocardiography, single photon emission computed tomography (SPECT), and F-18 fluorodeoxyglucose cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks. Iodine-123 meta-iodobenzylguanidine (MIBG) scan was done at 6 weeks for visualization of cardiac sympathetic activity. Left ventricular function and volumes at 4 weeks were similar between the 5 groups. No difference was observed in groups 2 to 5 in SPECT perfusion defect, matched and mismatched segments between SPECT and PET at 1 week and 4 weeks. MIBG scan showed similar uptake between the 5 groups. Pathologic analysis showed similar infarct size in groups 2 to 5. Infarct size reduction was not observed with use of fimasartan as well as other ACEI and ARB in a porcine model of acute MI.

Topics: 3-Iodobenzylguanidine; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anterior Wall Myocardial Infarction; Biphenyl Compounds; Cardiotonic Agents; Disease Models, Animal; Echocardiography; Fluorodeoxyglucose F18; Perindopril; Positron-Emission Tomography; Pyrimidines; Random Allocation; Swine; Tetrazoles; Tomography, Emission-Computed, Single-Photon; Valsartan; Ventricular Function, Left

To evaluate the effect of the novel angiotensin receptor blocker Fimasartan on the development of atherosclerosis and plaque stabilization in an animal model.. Twenty-four rabbits received an aortic balloon injury from 30 cm to a level just above the aortic valve to the iliac bifurcation using 3 Fr Fogarty catheters on third day of the experiment, followed by a 1% cholesterol diet for 8 weeks. The rabbits were randomized to receive placebo or 3 or 6 mg · kg⁻¹ · d⁻¹ Fimasartan. The study was double blinded. The rabbits started receiving their medications 2 days before the aortic balloon injury and treatment continued. Atherosclerosis burden was determined by calculating the intima-media ratio of the infrarenal portion of the aorta because the bulk of the atherosclerotic burden was limited to the infrarenal region. The frequency of plaque disruption with thrombosis and the proportions of the plaques that were occupied by macrophages, smooth muscle cells, and collagen were determined.. Relative to the placebo group, the Fimasartan-treated rabbits had less atherosclerosis [intima-media ratio (mean ± SEM) of 1.14 ± 0.21 vs. 1.51 ± 0.26, P = 0.005], fewer disrupted plaques with thrombi (3 of 16 vs. 5 of 8, P = 0.047), lower proportion of macrophages (17.5% ± 2.5% vs. 26% ± 3.5%, P = 0.03), higher proportion of smooth muscle cells (43.5% ± 8.3% vs. 11.9% ± 2.1%, P = 0.001), and higher proportion of collagen (34.3% ± 6.4% vs. 19.7% ± 2.1%, P = 0.02).. These results show that the newly developed angiotensin receptor blocker, Fimasartan, attenuated atherosclerosis progression and reduced macrophage accumulation in the rabbit aortic plaques.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Aorta, Abdominal; Atherosclerosis; Biphenyl Compounds; Cardiovascular Agents; Collagen; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Macrophages; Myocytes, Smooth Muscle; Plaque, Atherosclerotic; Pyrimidines; Rabbits; Random Allocation; Tetrazoles; Tunica Intima; Tunica Media