Current Opinion in Investigational Drugs

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6 Current Opinion in Investigational Drugs 2006 Vol 7 No 1 JAPAN HEALTH SCIENCE FOUNDATION; UNIVERSITY OF TOKUSHIMA Agent for controlling cholesterol homeostasis-associated gene transcription activity mediated by FXR activation. WO-2005097097 (20 October 2005) • Two of the inventors are based at Tokushima Bunri University, and all are named on WO-2005092328, which disclosed bis(bibenzyl) cyclic ether derivatives as farnesoid X-receptor (FXR) activators, useful for the treatment of hyperlipidemia. THERAPTOSIS SA Caspase-2 inhibitors and their biological applications. WO-2005105829 (10 November 2005) • Novel caspase-2 inhibitors and their use for treating ischemia are claimed. Several of these inventors claimed double-stranded RNA molecules with this activity in WO- 2004103389.
Patent alert Patent alert provides abstracts and expert commentary on a selection of recent patents that have been identified as being of particular interest. Selections are based on patent abstracts featured in patent products published by Thomson Scientific. Current opinions are provided based on the novelty of the invention and its potential application. Current Opinion in Investigational Drugs 2006 7(1):7-13 © The Thomson Corporation ISSN 1472-4472 Contents 7 Anti-inflammatory & immunomodulatory 8 Cardiovascular & renal 9 Central & peripheral nervous system 10 Endocrine & metabolics 12 Oncological Anti-inflammatory & immunomodulatory Selected by Clifford Whelan (Phlogopharm Ltd, Hatfield, Hertfordshire, UK) New C5a receptor inhibitory compounds - useful for treating, eg, inflammation and S aureus infections ALLIGATOR BIOSCIENCE AB (PUBL) (Van Strijp JAD, De Haas CJC, Kemmink J, Van Kessel KPM) WO-2005100385, 27 October 2005 Compounds for preventing intramolecular contact of Nterminal residues 10 to 18 of human C5aR with the extracellular loops, are claimed. Also claimed are further compositions and use of the compounds for treating conditions involving the C5a receptor on cells other than neutrophils, monocytes and endothelial cells, for example, inflammation, and for use in therapeutic vaccines for infections caused by chemotaxis inhibitory protein from Staphylococcus aureus (CHIPS)producing bacteria. The agents are stated to be small enough for use in therapy. U937 cells expressing C5aR were incubated with increasing concentrations of CHIPS31-121 or CHIPS31-121 mutant compounds. The samples were further incubated with 10 µg/ml of FITC-labeled anti-C5aR S5/1 monoclonal antibody. The IC50 values of the CHIPS31-121 mutants, in which single amino acids were substituted into alanines, were calculated. The CHIPS31-121 mutants with the lowest IC50 values (ng/ml) were N47 (5), R46 (10), Y121 deleted (10), K54 (10), K50 (10), G102 (12) and K101 (15). Chemical sequences are provided in the source document. Current Opinion S aureus is a common member of the bacterial flora on human skin. Although its presence is usually symptom free, it can cause a number of pathologies, ranging from superficial pustules to major life-threatening infections. Furthermore, the evolution of strains of S aureus that are resistant to antibiotic therapy makes the development of novel approaches to the treatment of infection an important therapeutic target. Neutrophil accumulation at the site of inflammation and infection is a hallmark of acute inflammation. Neutrophil chemotaxis can result from a wide range of compounds and this may have physiological importance. However, major chemoattractants in acute inflammation are complement products formed from plasma protein. This disclosure describes a series of proteins that inhibit binding of the complement product C5a to its receptor. The proteins described are based on an endogenous protein released by S aureus. Such proteins are likely to reduce neutrophil accumulation in vivo and may even be of benefit in inflammatory diseases, such as chronic obstructive pulmonary disease, in which products released by activated neutrophils appear to initiate changes that are not beneficial. However, in infection, particularly that characterized by abscess formation, neutrophil chemotaxis appears to contain the infection, and patients who are deficient in complement products seem to suffer severe infections. Thus, further research is required to determine whether the proteins described will have utility in the treatment of infection, and to determine how they can be utilized as anti-inflammatory agents. New imidazole compounds are H4 receptor inhibitors - useful for the inhibition of leukocyte recruitment and for the treatment of inflammation and immune disorders JANSSEN PHARMACEUTICA NV (Buzard DJ, Edwards JP, Kindrachuk DE, Venable JD) WO-2005092066, 06 October 2005 New imidazole compounds are claimed, as well as their use as H4 receptor inhibitors for the inhibition of leukocyte recruitment and for the treatment of inflammation. The compounds are claimed to be useful for the treatment of inflammatory response (eg, to chemotherapy or infection), allergy, dermatological disorders, autoimmune disease, lymphatic disorders, immunodeficiency, asthma, chronic obstructive pulmonary disease, atherosclerosis, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis). The compounds can also be isotopically labeled and used in diagnostic imaging. No suitable advantage is given. The illustrated compound had a Ki value of 6 nM when tested in vitro for its ability to bind to human histamine H4 receptors expressed by SK-N-MC or COS7 cells. Seventy specific compounds are claimed, including 1-(3-[4-[4,5-bis-(3-methoxyphenyl)-1Himidazol-2-yl]-3-chlorophenoxy]propyl)-4-methyl[1,4]diazepane. C H 3 O O CH3 H N Cl O N WO-2005092066 (Janssen) Current Opinion Leukocyte accumulation is one of the hallmarks of inflammation. Generally in the lesion, granulocytes and macrophages act as effector cells and lymphocytes act to orchestrate the response. Many reports in the literature suggest N N CH 3 7
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Erratum Current Opinion in Investig
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