Synthesis of a novel series of benzocycloalkene derivatives as melatonin receptor agonists

We synthesized a novel series of benzocycloalkene derivatives and evaluated their binding affinities to melatonin receptors. To control the spatial position of the amide group, one of the important pharmacophores, we incorporated an endo double bond, an exo double bond (E- and Z-configurations), and a chiral center (R- and S-configurations) at position 1. The indan derivatives with the S-configuration at position 1 were the most promising in terms of potency and selectivity for the human melatonin receptor (MT(1) site), while compounds with the R-configuration showed little potential. Our next attempt was to investigate the most favorable conformation of the methoxy group, the other important pharmacophore for binding to the MT(1) receptor. The introduction of a methyl group at position 5 of the indene ring conserved affinity; however, at position 7, it caused a decrease in affinity. These results suggested that the substitution at position 7 forced the methoxy group to adopt an unfavorable orientation. The optimization of the condensed ring size and substituents led to (S)-8d [(S)-N-[2-(2,3-dihydro-6-methoxy-1H-inden-1-yl)ethyl]propionamide], which had high affinity for the human MT(1) receptor (K(i) = 0.041 nM) but no significant affinity for the hamster MT(3)receptor (K(i) = 3570 nM). In addition, a practical synthetic method of chiral N-[2-(2,3-dihydro-1H-inden-1-yl)ethyl]alkanamides employing asymmetric hydrogenation with (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl-Ru has been established.     

The neurobiological approaches to obsessive-compulsive disorder]

The lifetime prevalence rate of obsessive-compulsive disorder (OCD) is more than 2 percent of the population. Its contemporary pathophysiological models have been explored. As serotonin reuptake inhibitors and cognitive behavior therapy are both considered first-line treatments of OCD, the treatment interventions provide us with clues. In this review, the authors summarized that genetics, neuropathology in the cortico-striatal-thalamic-cortical (CTSC) circuits, the association between OCD and Tourette's syndrome, the possibility of autoimmune-mediated pathophysiology containing PANDAS, serologic surveys of patients, and animal models including transgenic mice. Further research, genetic, neuroimmunological, and neuroimaging works may ultimately be useful in developing new treatments of OCD.     

Phencyclidine-induced cognitive deficits in mice are improved by subsequent subchronic administration of the glycine transporter-1 inhibitor NFPS and d-serine

Accumulating evidence suggests that the glycine modulatory site on the NMDA receptor could be potential therapeutic target for cognitive deficits in schizophrenia. The present study was undertaken to examine the effects of the glycine transporter-1 (GlyT-1) inhibitor, (R)-(N-[3-(4'-fluorophenyl)-3-(4'-phenylphenoxy)propyl])sarcosine (NFPS), on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (2-week) administration of NFPS (1.0 and 3.0 mg/kg/day) or D-serine (600 mg/kg/day). However, PCP-induced cognitive deficits were not improved by a single administration of NFPS (3.0 mg/kg). Furthermore, Western blot analysis revealed that levels of GlyT-1 in the hippocampus, but not frontal cortex, of the PCP (10 mg/kg/day for 10 days)-treated mice were significantly higher than those of saline-treated mice. An in vivo microdialysis study revealed that repeated PCP administration significantly decreased the extracellular levels of glycine in the hippocampus, but not frontal cortex, of mice. These findings suggest that repeated PCP administration increased the density of GlyT-1 in the hippocampus of mouse brain, and that the GlyT-1 inhibitor NFPS could ameliorate cognitive deficits in mice after repeated administration of PCP.     

A patient who underwent surgical treatment of an adult-type aneurysm in the nonpatent arterial duct

Adult-type aneurysms in the arterial duct are rare, and their spontaneous prognosis is poor. We performed surgical treatment of an aneurysm in the arterial duct in a 62-year-old male. The patient had had hoarseness since November 2003, and was referred to our hospital in March 2004. Thoracic CT and aortography demonstrated a sacciform aneurysm in the aorta in the distal arch region on the lesser curvature side. The patient was diagnosed as having an adult-type aneurysm in the nonpatent arterial duct, and underwent surgical treatment in April 2004. Thoracotomy in the fourth left intercostal space was performed up to the thoracic aorta, and a sacciform aneurysm, measuring 35 mm x 32 mm, was detected in the arterial duct. The recurrent laryngeal nerve adhering to the front surface of the aneurysm was overextended. Under partial extracorporeal circulation, the aneurysm was excised, and replaced by an artificial blood vessel. The postoperative course was satisfactory, and the patient was discharged from the hospital 14 days after surgery. The surgical outcome was good, and the hoarseness was improved. Taking possible complications into consideration, surgical treatment can be recommended in the early stage.     

Selected High-Risk Patients With Upper Tract Urothelial Carcinoma Treated With Radical Nephroureterectomy for Adjuvant Chemotherapy: A Multi-Institutional Retrospective Study

Background

No definitive evidence exists regarding use of adjuvant chemotherapy (AC) for high-risk cases after radical nephroureterectomy (RNU), and the benefit of AC remains controversial. The aims of this study were to evaluate the efficacy of AC in patients with upper tract urothelial carcinoma (UTUC) and to determine those who qualified for AC.

Dose‐finding study of the checkpoint kinase 1 inhibitor,prexasertib, in Japanese patients with advanced solid tumors

Prexasertib is a novel inhibitor of checkpoint kinase 1. The primary objective of this study was to evaluate prexasertib tolerability in Japanese patients with advanced solid tumors. This nonrandomized single‐arm open‐label phase 1 study of prexasertib consisted of 2 dose levels, 80 mg/m² and the global‐recommended dose based on a US study of 105 mg/m², administered intravenously once every 14 days (n = 6 for each dose). Transition to the higher dose proceeded if the frequency of dose‐limiting toxicity observed in cycle 1 was <33% at the lower dose. Safety measures, pharmacokinetics and antitumor activity were assessed. A total of 12 patients were treated. Two patients, one in each dose group, experienced dose‐limiting toxicities of febrile neutropenia, one grade 4 and the other grade 3; both patients recovered and continued the study treatment. The grade 4 treatment‐emergent adverse events related to study treatment were neutropenia (6 patients [50.0%]), leukopenia (4 patients [33.3%]), and 1 instance each (8.3%) of anemia, febrile neutropenia and thrombocytopenia. Neutropenia was generally transient and reversible; 11 patients (91.7%) required granulocyte colony‐stimulating factor treatment during the study. There were no discontinuations due to adverse events or deaths. The prexasertib pharmacokinetics displayed dose‐independent and time‐independent behavior across both dose levels, similar to the profile observed in the US‐based phase 1 study. Eight patients had a best overall response of stable disease. These data are consistent with the known safety profile for prexasertib and confirm its tolerability in Japanese patients with advanced solid tumors.     

Expression of MUC5AC and MUC6 in invasive ductal carcinoma of the pancreas and relationship with prognosis

Aim/Background. MUC5AC and MUC6 are two major types of mucin that are abundantly present in the stomach; both of them form a gel of high viscosity that provides protection and lubrication. Expressions of MUC5AC and MUC6 are seen in pancreatic neoplasms, whereas the relationships between MUC5AC/MUC6 expression and clinicopathological factors and patient prognosis in invasive ductal carcinoma (IDC) of the pancreas have not been investigated. The aim of this study was to investigate MUC5AC and MUC6 expressions in IDC with special reference to clinicopathological factors and patient prognosis. Methods. Tissue samples were taken from 33 patients with IDC of the pancreas after radical surgical treatment. MUC5AC and MUC6 expressions were examined immunohistochemically. Results. The expressions of MUC5AC and MUC6 were observed in the cytoplasm of the tumor cells. MUC5AC and MUC6 immunoreactivities in the cancer tissues were found in 21 (63.6%) and 15 (45.5%) of 33 cases of IDC of the pancreas, respectively. MUC5AC-negative expression was associated significantly with lymphatic invasion, venous invasion, lymph node metastasis, and MUC5AC-positive patients showed significant better survival than those MUC5AC-negative patients. MUC6 expression was significantly related to tumor location, whereas MUC6 expression did not show significant relationship with patient survival. Conclusion. The results indicate that MUC5AC expression plays an important role in impacting tumor progression in IDC of the pancreas. MUC5AC expression is a benefit to better survival of patients with IDC of the pancreas. MUC6 expression is not involved in tumor progression in IDC of the pancreas.     

Anti-carbonic anhydrase II antibody in autoimmune pancreatitis and tubulointerstitial nephritis

Nephrol Dial Transplant 2007; 22: 1273–1275;