The role of histaminergic neurotransmission in the promotion of waking has been extensively studied in preclinical species. Appreciation for the role of histamine continues to expand with increasing understanding of the interaction of histamine within the broad network of neuromodulators that regulate sleep and wake. The effects of histamine on waking are transduced through the H(1) and the H(3) receptors in the central nervous system. Brain penetrant over-the-counter antihistamines comprised of antagonist actions at H(1) receptors as well as varying degrees of antimuscarinic properties are marketed as sleep aids, based on their well-known daytime drowsiness side effects. The data supporting their use as sedatives, however, are not consistent. H(3) receptors are presynaptic receptors that limit histamine release as well as that of monoamine neurotransmitters thought to participate in the maintenance of waking. In this review, we discuss the existing studies on various antihistamines and antagonists of the H(1) receptor in the regulation of sleep in preclinical studies, normal subjects and in subjects with sleep disorders. In addition, we review the current data available on the use of ligands at H(3) receptors for the modulation of sleep and wake.

Gamma secretase modulators that acutely reduce soluble Aβ 42 levels in non-transgenic rodents

作者: Leventhal, Liza ; Nolan, Scott ; Mueller, Ralf ; Tu, Zhiming ; Vulsteke, Veerle ; Baruah, Bipul ; Patzke, Holger ; Koenig, Gerhard ; Hodgdon, Hilliary ; Sigel, Eric ; Ahlijanian, Michael ; Shapiro, Gideon ; De Strooper, Bart ; Catana, Florentina ; Nikonov, George ; Felsenstein, Kevin ; Miller, Mary Jo ; Wen, Melody ; Yang, Zhiyong ; Zhang, Mianji ; Bobrov, Sergey ; Costa, Don ; Hrdlicka, Lori ; Hopp, Sarah ; Rogers, Kathy ; Spaulding, Darcie ; Sarma, Bugga V. ; Chesworth, Richard ; Albayya, Faris ; Huang, Guangfei ; Lee, Winnie

The lowering of neurotoxic Aβ peptide production from APP (Amyloid Precursor Protein) has been the focus of multiple drug discovery efforts over the last decade for the treatment of Alzheimer′s disease (AD).The APP processing enzyme, gamma secretase (GS) is an attractive target that is particularly amenable to brain penetrant small mol. drug discovery.Direct gamma secretase inhibitors (GSIs) decrease Aβ production in animal models and humans.However, the clin. development of GSIs has been hampered by limiting side effects associated with this mechanism of action.In particular, GSIs also inhibit GS-mediated Notch processing, which results in gastrointestinal toxicity.These safety concerns have led to the discovery of gamma secretase modulators which selectively inhibit the production of the toxic Aβ42 peptide while maintaining total Aβ peptide levels and sparing Notch.A review of the SAR of a compound series which led to the discovery of EVP-14936, an orally bioavailable, CNS-penetrant GSM will be presented.

Alpha7 agonists for the treatment of cognitive disorders

作者: Koenig, Gerhard ; Hilt, Dana C. ; Gawryl, Maria

项与 EnVivo Pharmaceuticals 相关的新闻（医药）

2010-05-11

·BioSpace

EnVivo Pharmaceuticals, Inc. Initiates Phase IIb Alzheimer's Disease Trial For EVP-6124

WATERTOWN, Mass., May 11 /PRNewswire/ -- EnVivo Pharmaceuticals today announced the initiation and dosing of patients in a Phase IIb study of its EVP-6124 compound, a selective alpha-7 nicotinic agonist in patients with mild to moderate Alzheimer's disease. The multi-center, dose ranging, placebo controlled, six-month study taking place in the U.S. and Europe is designed to determine the safety and efficacy of EVP-6124 in producing procognitive effects and improving the clinical condition of Alzheimer's disease patients. "Patients with Alzheimer's disease have a number of symptomatic therapies available to them. However, the effects of the available medications are modest. Even if significant progress is made in slowing disease progression, more effective therapies that sustainably improve the cognition of the patients are clearly needed," said Kees Been, EnVivo president and CEO. "There is growing consensus that alpha-7 nicotinic agonists can potentially improve the cognitive function in Alzheimer's disease patients as evidenced by the number of large pharmaceutical companies advancing similar drugs through development. The potential upside for patients is considerable and we look forward to completing our Alzheimer's disease study by the middle of next year." The Phase IIb study will enroll mild to moderate Alzheimer's disease patients who will be randomized to three separate doses of EVP-6124 or placebo over six months. Efficacy will primarily be determined by the ADAS-Cog scale, a commonly used and accepted measure of cognition in patients with Alzheimer's disease. Secondary assessments will include other cognitive and clinical measures. EVP-6124 also is being tested in patients with schizophrenia in a separate Phase IIb study that started in late 2009. Two previous studies with EVP-6124 in Alzheimer's disease patients demonstrated that it was well tolerated and produced significant effects on a variety of cognitive measures of brain function such as attention, memory and executive function (complex thinking tasks). EVP-6124 had procognitive effects in two separate clinical trials: one study conducted in Alzheimer's disease patients already treated with Acetyl Choline Esterase Inhibitors (AChEI) and one in Alzheimer's disease patients not on AChEI therapy (naive patients). EVP-6124 is a selective agonist for the alpha-7 subtype of the nicotinic acetylcholine receptor and is being developed by EnVivo for potential cognitive enhancement in both schizophrenia and Alzheimer's patients. It has been shown to have excellent CNS penetration, oral bioavailability, pharmacokinetics and metabolic profile. About EnVivo Pharmaceuticals EnVivo Pharmaceuticals, located in Watertown, Mass., is a biopharmaceutical company dedicated to discovering and developing small molecule therapeutics for disorders of the central nervous system, with a current focus on Alzheimer's disease, cognitive disorders and schizophrenia. The company's lead product is an alpha-7 nicotinic acetylcholine receptor agonist and has been tested in Phase IIa clinical trials for cognition disorders in Alzheimer's disease and schizophrenia. The company's other programs include an epigenetics program based on Histone Deacetylase inhibition (HDACi) with EVP-0334 as the lead molecule for cognition in Alzheimer's disease which has completed Phase I studies, and several preclinical programs such as a Gamma Secretase Modulator (for Alzheimer's disease) and a PDE10 inhibitor program (for schizophrenia). For more information about EnVivo, visit . SOURCE EnVivo Pharmaceuticals

小分子药物

2008-02-06

·BioSpace

MethylGene Opts-Out of Collaboration with EnVivo Pharmaceuticals, Inc.

Montreal, Quebec and Watertown, Massachusetts. February 6, 2008 - MethylGene Inc. (TSX:MYG) and EnVivo Pharmaceuticals today announced that MethylGene has exercised its right to opt-out of further funding in its collaboration with EnVivo signed in February 2005. EnVivo will continue to research and develop histone deacetylase (HDAC) inhibitors for neurodegenerative disorders such as Huntington’s, Alzheimer’s and Parkinson’s diseases under license from MethylGene. A lead compound has been identified during the collaboration and designated as a clinical candidate by EnVivo. MethylGene will receive royalties on net sales of any approved product as well as a share of any sublicense income from future partnerships EnVivo may enter into with other companies for neurodegenerative programs. “The collaboration with EnVivo has been successful in leveraging our library of HDAC inhibitors beyond oncology. A lead candidate has been identified and we expect EnVivo will move this compound into clinical trials later this year. MethylGene has decided to exercise its right to opt out of the collaboration at the development stage for this non-core indication in order to strategically focus resources on our oncology development programs and other preclinical programs,” said Donald F. Corcoran, President and Chief Executive Officer of MethylGene. “We wish EnVivo well with the program and look forward to the opportunity to participate in the upside potential.” “The collaboration has been very productive and has provided us with a rich base from which we can move into several of the neurodegenerative diseases,” added Kees Been, President and Chief Executive Officer of EnVivo. “We look forward to advancing the lead compound towards clinical trials later this year. This would be the first brain-penetrant orally-available HDAC inhibitor that is being pursued for use as a cognition enhancing agent in neurodegenerative diseases with a potential for disease modification.” About MethylGene MethylGene Inc. (TSX: MYG) is a publicly-traded biopharmaceutical company focused on the discovery, development and commercialization of novel therapeutics for cancer. The Company's lead product, MGCD0103, is an oral isotype-selective HDAC inhibitor presently in multiple clinical trials for solid tumors and hematological malignancies, including Phase II monotherapy and Phase I and Phase II combination trials with Vidaza(R), Gemzar(R) and Taxotere(R). MGCD265 is an oral kinase inhibitor targeting the c-Met, Tie-2, Ron and VEGF receptor tyrosine kinases. In addition, MethylGene’s preclinical programs include: MGCD290 an HDAC inhibitor in combination with azoles for fungal infections and a sirtuins program for cancer. MethylGene's development and commercialization partners include Pharmion Corporation, Taiho Pharmaceutical and EnVivo Pharmaceuticals. Please visit our website at About EnVivo Pharmaceuticals EnVivo Pharmaceuticals (located in Watertown, MA) is a biopharmaceutical company dedicated to discovering and developing small molecule therapeutics for disorders of the central nervous system (CNS), currently focusing on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and cognition. The Company’s lead program, a Nicotinic Acetylcholine Receptor Agonist Program for cognition disorders in Alzheimer’s disease and Schizophrenia, has completed Phase I clinical testing. The Company’s preclinical programs include a Histone Deacetylase inhibitor (HDACi) program for Huntington’s disease, a Gamma Secretase Modulator program, and a PDE10 inhibitor program. For more information about EnVivo, please visit Investor Relations Contacts: MethylGene Inc. Rhonda Chiger Rx Communications Group, LLC Phone: 917-322-2569 rchiger@rxir.com Donald F. Corcoran President & CEO MethylGene Inc. Phone: 514-337-3333 ext. 373 mctavishk@methylgene.com EnVivo Pharmaceuticals Inc. Kees Been President & CEO EnVivo Pharmaceuticals Inc. Phone: 617-225-4250 kbeen@envivopharma.com

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