Synthesis, SAR study, and biological evaluation of novel 2,3-dihydro-1H-imidazo[1,2-a]benzimidazole derivatives as phosphodiesterase 10A inhibitors.

Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.

Impact of polyvascular disease on clinical outcomes in patients undergoing coronary revascularization: an observation from the CREDO-Kyoto Registry Cohort-2.

OBJECTIVE: Patients with coronary artery disease (CAD) often have prior stroke or concomitant extra-cardiac vascular disease (EVD) such as cerebral, aortic, or peripheral vascular disease. However, clinical outcomes after coronary revascularization in patients with polyvascular disease have not been fully elucidated. METHODS: Among 15,263 patients undergoing first coronary revascularization enrolled in the CREDO-Kyoto registry Cohort-2 from January 2005 to December 2007, there were 1443 patients with prior stroke (stroke + CAD group), 974 patients with EVD (EVD + CAD group), 253 patients with both prior stroke and EVD (stroke/EVD/CAD group) and 12,593 patients with neither prior stroke nor EVD (CAD alone group [reference]). RESULTS: The cumulative incidence of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction and stroke) through 3 years was significantly higher in patients with polyvascular disease compared with reference patients (19.9% in the stroke + CAD group, 18.5% in the EVD + CAD group, 20.1% in the stroke/EVD/CAD group, and 11.2% in the CAD alone group, P < 0.0001). After adjusting confounders, the presence of EVD and/or stroke was independently associated with higher risk for MACE compared with the reference group (adjusted HR [95%CI]: 1.34 [1.17-1.54], P < 0.0001 in the stroke + CAD group, 1.56 [1.32-1.84], P < 0.0001 in the EVD + CAD group, and 1.66 [1.24-2.23], P = 0.0007 in the stroke/EVD/CAD group). However, the presence of EVD and/or stroke was not associated with higher risk for myocardial infarction. CONCLUSIONS: Clinical outcome after coronary revascularization was worse in patients with prior stroke and/or EVD, which was mainly driven by the increased risk for non-coronary cardiovascular events.

A novel glycine transporter-1 (GlyT1) inhibitor, ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole), improves cognition in animal models of cognitive impairment in schizophrenia and Alzheimer's disease.

Hypofunction of brain N-methyl-d-aspartate (NMDA) receptors has been implicated in psychiatric disorders such as schizophrenia and Alzheimer's disease. Inhibition of glycine transporter-1 (GlyT1) is expected to increase glycine, a co-agonist of the NMDA receptor and, consequently, to facilitate NMDA receptor function. We have identified ASP2535 (4-[3-isopropyl-5-(6-phenyl-3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,1,3-benzoxadiazole) as a novel GlyT1 inhibitor, and here describe our in vitro and in vivo characterization of this compound. ASP2535 potently inhibited rat GlyT1 (IC(50)=92 nM) with 50-fold selectivity over rat glycine transporter-2 (GlyT2). It showed minimal affinity for many other receptors except for µ-opioid receptors (IC(50)=1.83 µM). Oral administration of ASP2535 dose-dependently inhibited ex vivo [(3)H]-glycine uptake in mouse cortical homogenate, suggesting good brain permeability. This profile was confirmed by pharmacokinetic analysis. We then evaluated the effect of ASP2535 on animal models of cognitive impairment in schizophrenia and Alzheimer's disease. Working memory deficit in MK-801-treated mice and visual learning deficit in neonatally phencyclidine (PCP)-treated mice were both attenuated by ASP2535 (0.3-3mg/kg, p.o. and 0.3-1mg/kg, p.o., respectively). ASP2535 (1-3mg/kg, p.o.) also improved the PCP-induced deficit in prepulse inhibition in rats. Moreover, the working memory deficit in scopolamine-treated mice and the spatial learning deficit in aged rats were both attenuated by ASP2535 (0.1-3mg/kg, p.o. and 0.1mg/kg, p.o., respectively). These studies provide compelling evidence that ASP2535 is a novel and centrally-active GlyT1 inhibitor that can improve cognitive impairment in animal models of schizophrenia and Alzheimer's disease, suggesting that ASP2535 may satisfy currently unmet medical needs for the treatment of these diseases.

Synthesis and biological evaluation of 3-biphenyl-4-yl-4-phenyl-4H-1,2,4-triazoles as novel glycine transporter 1 inhibitors.

We describe the preparation and evaluation of a novel series of glycine transporter 1 (GlyT1) inhibitors derived from a high-throughput screening hit. The SAR studies resulted in the discovery of 3-biphenyl-4-yl-4-(2-fluorophenyl)-5-isopropyl-4H-1,2,4-triazole (6p). A pharmacokinetic study was also conducted and revealed that 6p had excellent oral bioavailability and ameliorated learning impairment in passive avoidance tasks in mice.

Anxiolytic activity of a novel potent serotonin 5-HT2C receptor antagonist FR260010: a comparison with diazepam and buspirone.

Hyperfunction of brain 5-hydroxytryptamine(2C) (5-HT(2C)) receptor is suggested to be involved in anxiety as evidenced by the fact that a putative 5-HT(2C) receptor agonist 1-(m-chlorophenyl)-piperazine (m-CPP) causes anxiety in humans. We have recently identified FR260010 (N-[3-(4-methyl-1H-imidazol-1-yl)phenyl]-5,6-dihydrobenzo[h]quinazolin-4-amine dimethanesulfonate) as novel 5-HT(2C) receptor antagonist from diaryl amine derivatives, and here characterized in vitro and in vivo profiles of the compound. FR260010 showed high affinity for human 5-HT(2C) receptor (K(i): 1.10 nM) and high selectivity over 5-hydroxytryptamine(2A) (5-HT(2A)) receptor (K(i): 386 nM) and many other transmitter receptors. FR260010 showed antagonist activity at human 5-HT(2C) receptor in an intracellular calcium assay and showed no detectable intrinsic activity. The compound dose-dependently inhibited the hypolocomotion (ID(50): 1.89 mg/kg, p.o.) and hypophagia (ID(50): 2.84 mg/kg, p.o.) in rats induced by m-CPP, putative indices of brain 5-HT(2C) receptor antagonist activity. We then compared the effects of FR260010 with those of two other anxiolytics belonging to different classes, diazepam and buspirone, in anxiety models in rats and mice and adverse effect tests in mice. FR260010 (0.1-3.2 mg/kg, p.o.) and diazepam (1-10 mg/kg, p.o.) decreased behavioral indices of anxiety in all models, whereas buspirone (0.32-10 mg/kg, p.o.) did not significantly affect them in any models. In adverse effect tests, FR260010 and buspirone showed modest effects, whereas diazepam showed significant effects in all tests. These results suggest that FR260010 is a novel, potent, orally active and brain penetrable antagonist of 5-HT(2C) receptor, and may have therapeutic potential for treatment of anxiety, with more desirable profiles than benzodiazepines or 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonists.

Isolated right ventricular metastasis of uterine cervical carcinoma.

Isolated direct metastasis of uterine cervical carcinoma to the right ventricular endocardium is very rare. A 68-year-old woman was initially diagnosed as having stage IIIb squamous cell carcinoma of the uterine cervix, and was treated with radiation therapy. After 2 years, she developed heart failure and presented with a mass in the right ventricle. The results of further examinations were consistent with a tumor or a thrombus in the right ventricle. She underwent excision of the mass under cardiopulmonary bypass, and histopathologic examination of the resected tissue revealed metastatic squamous cell carcinoma of the uterine cervix. She was discharged 3 weeks after the operation, and underwent chemotherapy. However, she was readmitted with drug-induced interstitial pneumonia and died 5 months after the surgery. Patients with an intracardiac mass and a history of uterine cervical cancer should be suspected of having a myocardial metastasis until it is proven otherwise.

Successful treatment of chronic thromboembolic pulmonary hypertension with inhaled nitric oxide after right ventricular thrombectomy.

We report a case of a 42-year-old male with chronic thromboembolic pulmonary hypertension. His preoperative examination revealed severe hypoxemia (PaO2 48 mmHg, PaCO2 34 mmHg in room air), a mass in the right ventricle and severe pulmonary hypertension (pulmonary arterial pressure 70/33 mmHg). We successfully performed right ventricular thrombectomy to prevent further embolization from the right ventricular thrombus. Using inhaled low dose nitric oxide (NO) during perioperative period, weaning from cardiopulmonary bypass and ventilator were easily done. In this case, inhaled NO was successfully administered for the perioperative management of chronic pulmonary hypertension.

Surgical treatment for intrathoracic aneurysm of the innominate artery in an 83-year-old asymptomatic woman.

Aneurysm of the innominate artery is uncommon compared with other peripheral aneurysms, and holds the potential for rupture, embolization, or thrombosis as well as various complications caused by compression to the adjacent structures. The most effective treatment for this condition is surgical resection, but the earlier reports described high mortality rates. We report the case of an 83-year-old asymptomatic woman with an aneurysm in the innominate artery, which was successfully resected and repaired with the use of modern surgical techniques of hypothermic circulatory arrest and selective cerebral perfusion. Aggressive surgical intervention should be employed despite the fact that a patients is asymptomatic.