Arzneimittel-Forschung/Drug Research

A series of phthalazinedione bearing substituted oxadiazole moiety derivatives X(1-7) were synthesized in good yield and evaluated for their possible anticonvulsant activity. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. Their anticonvulsant activities were evaluated by the maximal electroshock induced seizure (MES) and subcutaneous pentylenetetrazole (PTZ) tests. All the tested compounds showed considerable anticonvulsant activities in at least one of the anticonvulsant tests. Moreover, some of the tested compounds exhibited moderate anticonvulsant activities in both MES and PTZ tests. From these results,[3-)2-Alkoxycarbonylmethylthioxadiozol-5-yl)methyl -6-Iodophthalazine - 1,4- (2H,3H)-1,4-dion] (X1-7) derivatives could be recommended as novel structures of broad spectrum anticonvulsants.

M. Zayed

R. Ayyad

Arzneimittelforschung

Some Novel Anticonvulsant Agents Derived from Phthalazinedione

一些来自邻苯二甲酰二酮的新型抗惊厥药物

G protein-coupled receptor 119 (GPCR 119 (GPR119)) agonists have received considerable attention as a promising therapeutic option for treatment of type 2 diabetes mellitus. GPR119 is one of the GPCRs expressed in pancreatic islet β-cells and its activation enhances stimulation of insulin secretion in a glucose-dependent manner. We have recently described a series of 6-amino-1H-indan-1-ones as potent, selective, and orally bioavailable GPR119 agonists with an amino group that plays important roles not only in their drug-like properties, such as high aqueous solubility, but also in their potent agonistic activity. However, many of these compounds displayed strong to moderate inhibition of human ether-à-go-go related gene channel. Attenuation of the basicity of the amino group by replacing the adjacent benzene ring with electron-deficient heteroaromatic rings provided several heterocyclic cores among which 6-aminofuro[3,2–c]pyridin-3(2H)-one was selected as a promising scaffold. Further optimization around the side chain moiety led to the discovery of 17i, which showed not only strong human GPR119 agonistic activity (EC50=14 nM), but also beneficial effects on gastric emptying and plasma total glucagon-like peptide-1 levels in mice.

M. Sakairi

M. Kogami

M. Torii

Y. Kuno

Y. Ohsawa

M. Makino

D. Kataoka

R. Okamoto

T. Miyazawa

M. Inoue

N. Takahashi

S. Harada

N. Watanabe

Synthesis and Biological Evaluation of a 6-Aminofuro[3,2–c]pyridin-3(2H)-one Series of GPR 119 Agonists

6-氨基呋喃[3,2-c]吡啶-3(2H)-酮系列GPR119激动剂的合成与生物学评价

VEGFR-2 tyrosine kinase inhibitors are currently receiving high interest in drug discovery process as anticancer agents. We have used virtual screening techniques in order to discover new scaffolds that can be used for developing new VEGFR-2 kinase inhibitors.Similarity ensemble approach was used to reduce the chemical space of ZINC database to select a subset of compounds. A validated structure-based pharmacophore was developed and adopted to screen the selected subset. Initial hits mapped to the pharmacophore were filtered using docking and scoring. Selected compounds were synthesized and biologically tested. Compound 9 showed very good cytotoxicity profile against the NCI 60 cancer cell lines, while compound 8 showed reasonable inhibition of VEGFR-2 tyrosine kinase.Stepwise virtual screening of databases such as ZINC may result in new scaffolds for developing VEGFR-2 kinase inhibitors.

M. Elsayed

M. El-Araby

R. Serya

K.A. Abouzid

Virtual Screening and Synthesis of New Chemical Scaffolds as VEGFR-2 Kinase Inhibitors

虚拟筛选与新化学骨架的合成作为VEGFR-2激酶抑制剂

To discover new bioactive lead compounds for medicinal purposes, herein, sulfone biscompounds bearing dihydrothiazoles (3-9, 14, 15), acrylamide (11), thiazolidinones (12, 13, 20), thiophenes (16, 17) and benzothiophene (19) were prepared and tested for their anticancer activity. The structures of the products were confirmed from elemental analysis as well as spectral data. All the synthesized compounds showed remarkable anticancer activity against human breast cancer cell line especially, compound (3) with IC50 value 23.02 µM which was better than that of Doxorubicin by three folds. In order to elucidate the mechanism of action of their cytotoxic activity molecular docking on the active sites of farnesyl transferase and arginine methyl transferase was performed for all synthesized compounds and good results were obtained.

M. Ghorab

M. Al-Said

Y. Nissan

Dapson in Heterocyclic Chemistry Part VI: Synthesis and Molecular Docking of Some Novel Sulfonebiscompounds of Expected Anticancer Activity

杂环化学中的达普森 第六部分：一些新型磺酰双化合物的合成及其分子对接与预期的抗癌活性

The main objective of this study was to investigate the pharmacokinetic characters of eszopiclone (CAS: 138729-47-2) after single and multiple-dose oral administration in healthy adult Chinese volunteers. In single-dose study, 12 subjects were given oral administrations of 1.5, 3 and 6 mg eszopiclone in an open-label, randomized, crossover fashion. In multiple-dose study, 8 subjects were given 3 mg eszopiclone once daily consecutively for 7 days. Blood samples were collected over 24 h and plasma eszopiclone were determined using a validated liquid chromatography/mass spectrometry (LC/MS/MS) assay. The safety and tolerability of eszopiclone was evaluated by adverse events recording, physical examination, laboratory testing, vital signs, and 12-lead ECG findings. The main pharmacokinetic parameters of eszopiclone after single-dose administration were as follows: doses of 1.5, 3 and 6 mg; Cmax of 18.08±4.65, 38.29±15.41 and 76.38±23.34 ng/ml; Tmax of 0.94±0.39, 1.04±0.63 and 1.08±0.51 h; AUC0–24 of 110.90±23.06, 227.36±62.41 and 504.10±140.13 ng*h/ml; elimination half-lives of 5.84±1.03, 5.53±1.91 and 6.17±1.23 h. After multiple-dose administration, the steady-state levels of eszopiclone were achieved by the 4th day, and the main pharmacokinetic parameters were Css_max at 33.43±5.63 ng/ml and AUCss (0–24) at 263.30±51.21 ng*h/ml. The most common adverse event was bitter or abnormal taste. All the adverse events were judged as mild to moderate and resolved without any medication. The pharmacokinetic character of eszopiclone is linear and dose-proportional over the range of 1.5–6 mg. The systemic exposure does not accumulate with once-daily administrations. Eszopiclone appears to have good safety and is well tolerated.

F. Wu

X. Zhao

M. Wei

S. Wang

H. Zhou

S. Guo

P. Zhang

Pharmacokinetics and Safety of Eszopiclone in Healthy Chinese Volunteers

健康中国志愿者中艾司佐匹克隆的药代动力学和安全性

Correction to: Wirksamkeit und Verträglichkeit eines pflanzlichen Arzneimittels mit Kapuzinerkressenkraut und Meerrettich bei akuter Sinusitis, akuter Bronchitis und akuter Blasenentzündung im Vergleich zu anderen Therapien unter den Bedingungen der täglichen PraxisArzneimittelforschung 2006; 56(03): 249-257DOI: 10.1055/s-0031-1296717

Karl-Heinz Goos

Uwe Albrecht

Berthold Schneider

Wirksamkeit und Verträglichkeit eines pflanzlichen Arzneimittels mit Kapuzinerkressenkraut und Meerrettich bei akuter Sinusitis, akuter Bronchitis und akuter Blasenentzündung im Vergleich zu anderen Therapien unter den Bedingungen der täglichen Praxis

植物药物毛蕊花和辣根治疗急性鼻窦炎、急性支气管炎和急性膀胱炎的疗效和耐受性在日常实践中与其他疗法的比较

Drei große Bereiche der Medizin erschließen sich der klinischen Immunintervention: die Tumorerkrankungen, die entzündlichen Erkrankungen inklusive der Autoimmunkrankheiten und die Transplantationsmedizin. Für das Paul-Martini-Symposium 2012 konnten herausragende Mediziner und Wissenschaftler in jedem dieser Bereiche gewonnen werden, die eine Bestandsaufnahme über neue immunstimulierende wie suppressive Therapien aus diesen 3 Fachgebieten vornehmen.

S. Endres

S. Meuer

P. Scriba

Klinische Immunintervention: aktuelle und künftige Ansätze

临床免疫干预：当前与未来方法

C-type lectin receptors (CLRs) that signal via the kinase Syk are an important class of pattern recognition receptors in the innate immune system. They recognize pathogen- and host-derived danger signals and drive several cellular responses, including phagocytosis, the production of reactive oxygen species (ROS), as well as altered gene expression. Best characterized is the role of CLR signaling in anti-fungal immunity, but accumulation evidence indicates additional essential functions for CLR activity in innate immunity against bacteria, viruses or parasites. Moreover, deregulated CLR signaling appears to contribute to inflammatory disease. Crucial for CLR-mediated inflammation and host defence are the engagement of NF-κB signaling pathway and inflammasome activation. NF-κB signaling by CLRs depends on the adapter protein Card9 that upon activation cooperates with Bcl10 and the paracaspase Malt1 to engage the canonical IKK pathway. This mechanism operates independent from CLR-induced ROS production and phagocytosis. Recent findings have indicated that PKCδ is the critical kinase which directly phosphorylates Card9 at Thr231 and which subsequently triggers the signal-induced association of Card9 with Bcl10 and Malt1 and the further recruitment of TAK1 for activation of the canonical NF-κB pathway. Moreover, Syk-mediated CLR signaling upon fungal recognition is crucial for IL-1β generation and is required for both proIL-1β synthesis and activation of the Nlrp3 inflammasome. While proIL-1β synthesis selectively requires the Card9 pathway, inflammasome activation by fungi involves ROS production and potassium efflux. Thus, there is cross talk between Syk-coupled CLRs and Nlrp3, at least in the context of fungal infection. In this symposium I will discuss recent insights into the molecular regulation of CLR-mediated inflammatory effector function and its potential role in human disease together with opportunities to therapeutically manipulate these pathways.

J. Ruland

C-type Lectin Receptors: Signaling and Therapeutic Opportunities

C型凝集素受体：信号传导与治疗机遇

Chronic inflammatory diseases fall into two categories: either "autoimmune" or "auto-inflammatory" [1]. Although nearly all autoimmune diseases have an inflammatory component, as in rheumatoid arthritis, in autoimmune diseases, the primary defect is the auto-reactive T-cell. The term "auto-inflammatory diseases" encompasses several local and systemic diseases due to monocyte dysfunction, each responsive to blocking interleukin-beta (IL-1β) or blocking the IL-1 receptor using the IL-1 receptor antagonist. The best example is Familial Mediterranean Fever since manifestations of this disease include fever, fatigue, painful inflamed serosal and synovial tissues, biochemical markers of systemic inflammation, and hematological responses of neutrophilia [2]. Other auto-inflammatory diseases are due to single amino acid mutations in the protein "cryopyrin" [3] and are called "cryopyrinopathies"; the same syndromes are also termed "cryopyrin associated periodic syndromes" (CAPS). Systemic inflammation can be lethal, and the best example is septic shock. However, septic shock represents exogenously induced inflammation or simply "exogenous inflammation." Although many laboratory studies use bacterial products to stimulate IL-1β production, in the clinical sense, auto-inflammation is the result of IL-1-induced IL-1 or IL-1 induction of other cytokines such as IL-17. Either IL-1α or IL-1β can be the driving component in auto-inflammation. For example, in patients with neonatal onset multi-inflammatory disease (NOMID) treatment with the IL-1 receptor antagonist anakinra drives down not only the manifestations of the disease but also gene expression for IL-1α, IL-1β, TNFα, IL-6 and caspase-1 [4]. The most compelling evidence for the importance of IL-1 in inflammation comes from persons born with a mutation in the gene that codes for the IL-1 receptor antagonist. The syndrome is called DIRA for deficiency of the IL-1 receptor antagonist [5], [6]. At birth, these patients develop lethal inflammation with massive numbers of neutrophils in the skin and high levels of IL-17.

C. Dinarello

Interleukin-1 and the Treatment of Auto-inflammatory Diseases

白细胞介素-1与自身炎症性疾病的治疗

T cell-engaging bispecific antibodies can transiently link with otherwise inactive cytotoxic T cells in patients' tumor cells and induce redirected potent lysis of tumor cells. One example for this is blinatumomab (AMG 103), a CD19/-CD3-bispecific BiTE® antibody used to treat acute lymphocytic leukemia (ALL) and non-Hodgkin's lymphoma (NHL), which is in an advanced stage of clinical development. Two other BiTE® antibodies, AMG 211/MEDI-565 (CEA/CD3-specific) and AMG 110 (EpCAM/CD3-specific), are in the early stages of clinical development to treat solid tumors. Blinatumomab and all other BiTE® antibodies have been shown to activate T cells in a highly conditional manner that was strictly dependent on the presence of target cells, effect the serial lysis of target cells by T cells, induce T cell proliferation, and act at sub-nanomolar concentrations. The mode of action of BiTE® will be described in detail and compared to other treatment modalities.

G. Zugmaier

Immunotherapy with BiTE® Antibodies: Lessons Learned from Blinatumomab

BiTE®抗体免疫疗法：从博纳吐单抗中汲取的经验教训

涉及主题	医学生物化学内科学药理学生物化学内分泌学遗传学有机化学心理学物理麻醉精神科
出版信息	出版商: Editio Cantor Verlag GmbH，出版周期: ，期刊类型: journal，开源期刊: 否
基本数据	创刊年份: 1951，原创研究文献占比: 0.00%，自引率:N.A.， Gold OA占比: 0.00%

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