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Pollitt A.Y.,University of Birmingham | Grygielska B.,University of Birmingham | Leblond B.,ExonHit Therapeutics | Desire L.,ExonHit Therapeutics | And 2 more authors.
Blood | Year: 2010

The C-type lectin-like receptor 2 (CLEC-2) activates platelets through Src and Syk tyrosine kinases via a single cytoplasmic YxxL motif known as a hem immunoreceptor tyrosine-based activation motif (hemITAM). Here, we demonstrate using sucrose gradient ultracentrifugation and methyl-β-cyclodextrin treatment that CLEC-2 translocates to lipid rafts upon ligand engagement and that translocation is essential for hemITAM phosphorylation and signal initiation. HemITAM phosphorylation, but not translocation, is also critically dependent on actin polymerization, Rac1 activation, and release of ADP and thromboxane A2 (TxA2). The role of ADP and TxA2 in mediating phosphorylation is dependent on ligand engagement and rac activation but is independent of platelet aggregation. In contrast, tyrosine phosphorylation of the GPVI-FcRγ-chain ITAM, which has 2 YxxL motifs, is independent of actin polymerization and secondary mediators. These results reveal a unique series of proximal events in CLEC-2 phosphorylation involving actin polymerization, secondary mediators, and Rac activation. © 2010 by The American Society of Hematology.


Trademark
Exonhit S.A. and ExonHit Therapeutics | Date: 2011-09-13

Chemical preparations and compositions, namely, nucleic acids attached to a solid medium, for industrial and scientific use; chemical fissile preparations for laboratory use; chemical fissile preparations for scientific research; chemical preparations for nucleic acids attached to a solid medium, other than for medical or veterinary purposes; biological preparations, other than for medical or veterinary purposes, namely, blood for enabling the quantification of nucleic acid content; chemicals for scientific use, other than for medical or veterinary purposes; chemical preparations or reagents for laboratory, namely, nucleic acid to screen and analyze gene expression, to identify therapeutic targets and products, and to conduct pharmacogenomic and genotoxicity research in the fields of pharmacology, food, chemistry, cosmetology, plant protection, and veterinary sciences; chemical preparations for scientific use, namely, nucleic acid libraries to screen and analyze gene expression, to identify therapeutic targets and products, and to conduct pharmacogenomic and genotoxicity research in the fields of pharmacology, food, chemistry, cosmetology, plant protection, and veterinary sciences; chemical preparations for scientific use, namely, DNA biochips for decoding genes affected by the Alzheimers disease or revealing the transcriptomic signature of patients affected with Alzheimers disease, and DNA chips to make visible and analyze gene expression in the fields of human and pharmacological medicine and veterinary science. Pharmaceutical preparations for treating neurodegenerative diseases, particularly Alzheimers disease; diagnostic reagents and media for medical use, namely, reagents and media for use in testing blood biomarkers, to enable the identification of patients suffering from Alzheimers disease or at risk of developing the disease and for enabling the identification of patients responding to specific treatments; acidic biological preparations and products for pharmaceutical purposes, namely, pharmaceutical preparations for diagnosing Alzheimers disease; capsules for diagnostic tests and medicines sold empty; chemico-pharmaceutical preparations for diagnosing, preventing and treating Alzheimers disease; biopharmaceutical preparations for diagnosing, preventing and treating Alzheimers disease; chemicals for medical, pharmaceutical or veterinary purposes, namely, chemicals for diagnosing neurodegenerative diseases, especially Alzheimers disease; medical and clinical diagnosis testing kits comprised of nucleic acid banks, nucleic acids on DNA chips and testing probes; DNA libraries and RNA libraries for medical diagnostic purposes; nucleic acid sequences for use on biochips, for medical and medical diagnostic use, namely, for decoding genes affected by Alzheimers disease or revealing the transcriptomic signature of patients suffering from Alzheimers disease; enzymes or enzyme preparations for medical or veterinary purposes, namely, enzyme stabilizers and enzyme substrates used as ingredients in medicines for treatment of Alzheimers disease; reagents contained in diagnostic test kits for taking blood samples, for the preservation of the biological material under analysis in order to carry out the test under the appropriate conditions. Surgical, medical, dental and veterinary apparatus and instruments, namely, apparatus and instruments for use in identifying, assessing the seriousness of, assessing the prognoses of, measuring the progression of and measuring the conversion of neurodegenerative diseases such as Alzheimers; medical apparatus using DNA chips for analyzing blood; apparatus for analyzing blood; apparatus for medical diagnostic purposes, namely, kits for taking blood samples comprising medical instruments for taking blood, DNA chips for diagnosing Alzheimers disease, and material required for the preservation of the biological material under analysis in order to carry out the test under the appropriate conditions; spoons for medicines; containers specially adapted for the application of medicines, namely, bags and pouches used in the delivery of medication; probes for medical purposes; syringes for medical purposes; galvanic therapeutic devices for diagnosing neurodegenerative diseases, especially Alzheimers disease. Research and development for others of pharmaceutical molecules or biological markers and medicines for diagnosing and treating neurodegenerative diseases; chemical analyses; chemical research; chemical services, namely, analysis of RNA genes, tissues, and blood samples; biotechnological project studies to identify people suffering from Alzheimers disease and to measure the seriousness, prognoses, progression and conversion of the disease and to determine how patients respond to treatments; research and development of new products for others; biological research; biotechnological research; technical research in the field of biotechnology; biotechnological analysis services; laboratory analyses, namely, quantification of nucleic acid content for medical and scientific research purposes. Medical services; veterinary services; medical assistance; consulting in the fields of biotechnology and pharmacy, namely, to assist in the selection of Alzheimers sufferers for clinical trials and to offer personalized treatments; hospitals; pharmacists services to make up prescriptions; pharmaceutical advice; medical services, namely, facilitating the diagnosis and care of geriatric patients and patients with neurodegenerative diseases; health care; telemedicine services.


Drott J.,NeuroDetective International | Desire L.,ExonHit Therapeutics | Drouin D.,ExonHit Therapeutics | Pando M.,ExonHit Therapeutics | Haun F.,NeuroDetective International
European Journal of Pharmacology | Year: 2010

Etazolate is a phosphodiesterase 4 (PDE4) inhibitor and GABAA receptor modulator that also stimulates alpha-secretase activity and neurotrophic soluble amyloid precursor protein (sAPPα) production, currently developed as a possible Alzheimer's disease therapeutic. In this study two doses of etazolate were tested for cognitive effects in normally aged rats, using a complex spatial learning and memory task that emphasized two naturally occurring behaviors in rodents, foraging for food and returning large pieces of found food to a safe home location. Both etazolate doses completely prevented both (1) a foraging deficit that developed in untreated aged rats over the course of the test, as well as (2) a trial-specific deficit in memory for previously visited food locations that also developed over the course of the test in untreated aged rats. Both doses also significantly reduced a separate memory deficit for changing locations of the animals' home box, plus completely prevented a significant tendency for untreated aged animals to attempt entry into similar-appearing but incorrect home boxes. The combined behavioral data demonstrate positive effects of etazolate on separate age-related cognitive deficits, using a complex task based on naturally occurring rodent behaviors. © 2010 Elsevier B.V.


The invention relates to compounds of the formula or a pharmaceutically acceptable salt thereof, wherein R, R^(1 )through R^(7 )and Ar are as defined herein. These compounds are useful as inhibitors of phosphodiesterase 10 (PDE10A) which are useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type II diabetes, metabolic syndrome, glucose intolerance, pain and ophthalmic diseases.


Patent
ExonHit Therapeutics and Allergan, Inc. | Date: 2012-02-17

The invention relates to compounds of the formula wherein R, R_(1), through R_(7 )and Ar are as defined herein. These compounds are useful as inhibitors of phosphodiesterase 10 (PDE10A) which are useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type II diabetes, metabolic syndrome, glucose intolerance, pain and ophthalmic diseases.


Patent
ExonHit Therapeutics and Allergan, Inc. | Date: 2012-02-16

Disclosed herein is a method of treating disorders of the retina comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I as defined herein. These compounds are useful as PDE10 inhibitors.


Patent
ExonHit Therapeutics | Date: 2012-03-28

The present invention relates to the fields of biology, genetics and medicine. In particular it concerns new methods for the detection, characterisation and/or treatment (or management) of neurodegenerative diseases, particularly amyotrophic lateral sclerosis. The invention equally concerns methods for identifying or screening compounds active in these diseases. The invention further concerns the compounds, genes, cells, plasmids or compositions useful for implementing the hereinabove methods. In particular, the invention describes the role of PDE4B in these diseases and its use as a therapeutic, diagnostic or experimental target.


Compounds of Formulas 1 and 2 where the variables have the meaning disclosed in the specification, have analgesic and in some cases immunostimulant activity.


Patent
ExonHit Therapeutics | Date: 2010-07-09

The present invention relates generally to the fields of genetics, biochemistry, medicinal chemistry and medicine. The present invention more particularly discloses the identification of a human gene variant involved in neuropathological conditions, and methods for the diagnosis, prevention and treatment of such diseases and related disorders, as well as for the screening of therapeutically active drugs. The present invention relates to catalytically active beta-secretase (Memapsin2, BACE) variants, and nucleic acids encoding them. The invention is useful in the identification of agents that inhibit the activity of a particular BACE isoform and thus agents and therapies affecting the genesis, development or progression of neuropathological conditions, including Alzheimers disease and dementia.


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