TAS05567, a Novel Potent and Selective Spleen Tyrosine Kinase Inhibitor, Abrogates Immunoglobulin-Mediated Autoimmune and Allergic Reactions in Rodent Models.

Spleen tyrosine kinase (Syk) is involved in regulation of B-cell receptor (BCR) and Fc receptor downstream signal pathways. Syk plays an essential role in production of inflammatory mediators and differentiation in various immune cells and is therefore an attractive target for treating inflammatory conditions, such as autoimmune and allergic diseases. We identified TAS05567 as a highly selective Syk inhibitor and evaluated its therapeutic potential in animal models. In vitro biochemical assays were performed with available kinase assay panels. Inhibitory effects of TAS05567 on immune cells were analyzed by assessing the Syk downstream signaling pathway and production of inflammatory factors. In vivo effects of TAS05567 were evaluated in animal models of autoimmune diseases and antigen-specific IgE transgenic mice. TAS05567 inhibited only 4 of 191 kinases tested but inhibited Syk enzymatic activity with high potency. TAS05567 inhibited BCR-dependent signal transduction in Ramos cells, FcγR-mediated tumor necrosis factor-α production in THP-1 cells, and FcεR-mediated histamine release from RBL-2H3 cells. In rheumatoid arthritis models, TAS05567 suppressed hind-paw swelling in a dose-dependent manner compared with vehicle. Moreover, TAS05667 markedly reduced histopathologic scores in an established rat arthritis model. In a mouse immune thrombocytopenic purpura model, platelet counts were reduced with injection of anti-platelet antibody. TAS05567 prevented the platelet count decrease in a dose-dependent manner. Finally, TAS05567 treatment suppressed IgE-mediated ear swelling in vivo. Collectively, our data indicate TAS05567 is a selective Syk inhibitor and potential therapeutic candidate for treating humoral immune-mediated inflammatory conditions such as autoimmune and allergic diseases.

[Trigger point therapy for myofascial pain in cancer patients (second report) analysis results of special use-results surveillance by neovitacain® injection].

Our first report mentioned the analysis results of the safety and efficacy of trigger point (TP) therapy by Neovitacain® injection (NV) in the daily clinical treatment of myofascial pain in cancer patients. This time, we report additional considerations regarding the following points; (1) Injection sites: they were concentrated on both sides of the spine, indicating that TPs could be easily formed on the points and near them to support the body's weight when patients were supine. (2) Correlation between VAS and FS: VAS and FS were positively correlated in every measurement period. (3) Patient satisfaction: many patients made several comments expressing feelings of satisfaction from this treatment. The comments were considered to reflect the patients' candid feelings. Therefore, all comments were classified according to the degree of patients' feeling of satisfaction. It may be possible to obtain much higher patient satisfaction by hearing out the voice of the patients. Judging from this study, TP therapy by NV for myofascial pain in cancer patients relieved the total pain of cancer patients. TP therapy has potential for obtaining high patient satisfaction.

[Two cases of interstitial pneumonia caused by cetuximab plus mFOLFOX6 therapy in metastatic colorectal cancer patients].

Case 1: A 69-year-old man was diagnosed with rectal cancer and liver metastasis. After low anterior resection, mFOLFOX6 plus cetuximab therapy was started for resection of the liver metastasis. However, he had to forgo liver resection because he developed acute exacerbation of interstitial pneumonitis (IP) after 6 courses of chemotherapy. Despite beginning the second-line treatment with mFOLFOX6 plus bevacizumab, he died in June 2012. Case 2: A 71-year-old man had undergone sigmoidectomy for sigmoid colon cancer in 2005, and right lower lobe partial resection for metastatic lung cancer in 2006. Although radiofrequency ablation or transcatheter arterial chemoembolization had been performed for multiple liver metastases several times since 2007, his multiple liver metastases were uncontrollable. Therefore, FOLFOX4 therapy was started in 2010, and mFOLFOX6 plus cetuximab therapy was substituted for FOLFOX4 therapy in 2011. The patient died in March 2012 due to the rapid development of IP, and thus, it appears that IP was the cause of death in both patients. The general condition, including pulmonary function, of patients at risk of IP must be checked before starting cetuximab therapy for metastatic colorectal cancer.

TAS1553, a small molecule subunit interaction inhibitor of ribonucleotide reductase, exhibits antitumor activity by causing DNA replication stress.

Ribonucleotide reductase (RNR) is composed of two non-identical subunits, R1 and R2, and plays a crucial role in balancing the cellular dNTP pool, establishing it as an attractive cancer target. Herein, we report the discovery of a highly potent and selective small-molecule inhibitor, TAS1553, targeting protein-protein interaction between R1 and R2. TAS1553 is also expected to demonstrate superior selectivity because it does not directly target free radical or a substrate binding site. TAS1553 has shown antiproliferative activity in human cancer cell lines, dramatically reducing the intracellular dATP pool and causing DNA replication stress. Furthermore, we identified SLFN11 as a biomarker that predicts the cytotoxic effect of TAS1553. Oral administration of TAS1553 demonstrated robust antitumor efficacy against both hematological and solid cancer xenograft tumors and also provided a significant survival benefit in an acute myelogenous leukemia model. Our findings strongly support the evaluation of TAS1553 in clinical trials.

Selective M3 muscarinic receptor antagonist inhibits small-cell lung carcinoma growth in a mouse orthotopic xenograft model.

In small cell lung carcinoma (SCLC), acetylcholine (ACh) is synthesized and secreted, and it acts as an autocrine growth factor through activation of its receptors, muscarinic receptor (mAChR) and nicotinic receptor (nAChR). Alteration of tumor growth by blockade of M(3) mAChR in a human SCLC cell line, NCI-H82, was investigated in the present study. We used a highly selective M(3) muscarinic antagonist, N-(2-[3-([3R]-1-(cyclohexylmethyl)-3-piperidinyl]methylamino)-3-oxopropyl]amino-2-oxoethyl)-3,3,3-triphenyl-propioamide (J-115311). Our results show that J-115311 inhibited the increased intracellular calcium elicited by carbachol, a muscarinic agonist, in SCLC cells. J-115311 also inhibited SCLC cell growth in vitro. In a mouse orthotopic xenograft model, J-115311 dose-dependently reduced tumor growth when NCI-H82 cells were inoculated into the upper left lobe of the lung. These findings indicate that blockade of M(3) mAChR can suppress tumor growth in SCLC, suggesting the potential therapeutic utility of M(3) muscarinic antagonists as anti-cancer agents.

[Trigger point therapy for myofascial pain in cancer patients (first report)-analysis results of special use-results surveillance by Neovitacain® injection-].

Special use-results surveillance was conducted to examine the safety and efficacy of trigger point (TP) therapy by Neovitacain ®injection (NV) in the daily clinical treatment of myofascial pain in cancer patients. The case report forms of 175 patients were collected from 43 nationwide facilities and all of them were analyzed in terms of safety and efficacy. This treatment deeply impressed both patients and physicians; 75.4% and 78.3% respectively, over "the good". In addition, as the results of Wilcoxon's signed rank sum test for pain assessment (VAS, FS), both "Cumulative effect before and after treatment" and "Immediate effect before and after each administration" were confirmed to show a highly significant difference (p<0. 0001). Side effects were observed in five of 175 cases (2. 9%) but none of them were serious. Judging from the results of this study, TP therapy with NV was considered to be very useful for the treatment of myofascial pain in cancer patients.

Discovery of novel 2-(pyridine-2-yl)-1H-benzimidazole derivatives as potent glucokinase activators.

The synthesis and structure-activity-relationships (SARs) of novel 2-(pyridine-2-yl)-1H-benzimidazole glucokinase activators are described. Systematic modification of benzimidazole lead 5a identified from a high-throughput screening led to the discovery of a potent and metabolically stable glucokinase activator 16p(R) with greater structural diversity from GKAs reported to date. The compound also demonstrated acute oral glucose lowering efficacy in rat OGTT model.

Syntheses and structure-activity relationships of novel, potent, and selective trans-2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists.

Syntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC(50)=3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC(50)=5.9 nM), both of which are potent, selective, and orally bioavailable Y5 receptor antagonists.

Design, syntheses, and structure-activity relationships of novel NPY Y5 receptor antagonists: 2-{3-Oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole derivatives.

Design, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k).

Pituitary abscess in a patient with painless thyroiditis.

The preoperative diagnosis of pituitary abscess is difficult. The case of a 56-year-old man with a pituitary abscess and painless thyroiditis is presented. There has been no previous such report. The differential diagnosis includes pituitary abscess, lymphocytic adenohypophysitis or infundibuloneurohypophysitis, share clinical symptoms of panhypopituitarism and diabetes insipidus, and is of critical importance as the treatment of these conditions differ. The association with painless thyroiditis suggests a diagnosis of lymphocytic adenohypophysitis or infundibuloneurohypophysitis. However, the coincidence of pituitary abscess and painless thyroiditis was observed in our patient, and thus though rare, should be considered. Surgical exploration and histopathological examination are essential for the differential diagnosis of these diseases.

An Unusual Case of Fulminant Type 1 Diabetes during the Second Trimester of Pregnancy.

Fulminant type 1 diabetes is a new subtype of rapid-onset type 1 diabetes, with pancreatic exocrine dysfunction, that usually develops during the third trimester of pregnancy. We describe a patient with fulminant type 1 diabetes onset during her second trimester, resulting in premature delivery. The 34-year-old woman, without any known risk factors for diabetes mellitus, experienced a sudden stillbirth at 24-weeks gestation. Her blood glucose level was 950 mg/dL and she was positive for urine ketone bodies. The condition met all the diagnostic criteria for fulminant type 1 diabetes, and was diagnosed as such. Although this disease is rare, its progression is rapid, and its clinical course is severe and occasionally leads to death; therefore, a full knowledge of the disease is important to facilitate an accurate diagnosis.

Modulation of neuropeptide Y receptors for the treatment of obesity.

BACKGROUND: Neuropeptide Y (NPY) has been demonstrated to have critical roles in the physiological control of appetite and energy homeostasis through NPY Y1, Y2, Y4 and Y5 receptors. A number of synthetic ligands for NPY receptor subtypes have been developed to date, with Y5 receptor antagonists and Y2 and Y4 receptor agonists advancing into clinical trials. METHODS: A survey of the scientific and patent literature since mid-2006 is presented. CONCLUSION: In addition to the specific modulation of respective NPY receptor subtypes, recent investigations have revealed that modulation of multiple NPY receptor subtypes produces additive or even synergistic anti-obesity effects. Development of reliable small molecule Y1, Y2 and Y4 receptor ligands would greatly accelerate investigations and drug discovery.

Long-term remission of cyclic Cushing's disease that was diagnosed and treated surgically in non-active phase.

Cyclic Cushing's disease is a rare clinical entity that is defined as a periodic excessive production of adrenocorticotropic hormone (ACTH) and cortisol. Only 42 cases with cyclic Cushing's disease have been reported in the literature. The diagnosis is very difficult because of the fluctuating secretion of ACTH and cortisol. We report a 78-year-old woman with a pituitary adenoma presenting with cyclic Cushing's disease. In the present case, several interesting issues are pointed out: 1) MRI study detected the presence of an adenoma and selective venous sampling in the cavernous sinus disclosed the hypersecretion of ACTH from a pituitary adenoma. These neuroimaging and endocrinological studies were helpful for the diagnosis, even in the remission phase. 2) The disease was in the long-term remission phase after transsphenoidal surgery despite the high recurrence rate in this clinical entity, although it recurred four years later. Even in the remission phase of cyclic Cushing's disease, meticulous endocrinological and neuroimaging examinations can reveal the presence of a pituitary adenoma, which should be treated surgically.

Discovery of 2-aminothiazole-4-carboxamides, a novel class of muscarinic M(3) selective antagonists, through solution-phase parallel synthesis.

Synthesis and structure-activity relationship of a new class of muscarinic M(3) selective antagonists were described. In the course of searching for a muscarinic M(3) antagonist with a structure distinct from those of the 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives, we identified a thiazole-4-carboxamide derivative (1) as a lead compound in our in-house chemical collection. Since this compound (1) showed relatively low binding affinity (K(i)=140 nM) for M(3) receptors in the human binding assays, we tried to improve its potency and selectivity for M(3) over M(1) and M(2) receptors by derivatization of 1 through a combinatorial approach. A solution-phase parallel synthesis effectively contributed to the optimization of each segment of 1. Thus, we have identified a cyclooctenylmethyl derivative (3e) and a cyclononenylmethyl derivative (3f) as representative M(3) selective antagonists in this class.

Muscarinic M(3) receptor antagonists with (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxyphenylacetamide Structures. Part 2.

Optimization of the amine part of our original muscarinic M(3) receptor antagonist 1 was performed to identify M(3) receptor antagonists that are superior to 1. Compounds carrying a variety of diamine moieties without hydrophobic substituent on the nitrogen atom were screened against the binding affinity for the M(3) receptor and the selectivity for M(3) over the M(1) and M(2) receptors. This process led to a 4-aminopiperidinamide (2l) with a K(i) value of 5.1 nM and with a selectivity of the M(3) receptor that was 46-fold greater than that of the M(2) receptor. Further derivatization of 2l by inserting a spacer group or by incorporating alkyl group(s) into the amine part resulted in the identification of an 4-(aminoethyl)piperidinamide 2l-b with a K(i) value of 3.7 nM for the M(3) receptor and a selectivity for the M(3) receptor that was 170-fold greater than that of the M(2) receptor.