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Okun I.,Avineuro Pharmaceuticals Inc. | Tkachenko S.E.,Avineuro Pharmaceuticals Inc. | Khvat A.,ChemDiv Inc. | Mitkin O.,Chemical Diversity Research Institute | And 2 more authors.
Current Alzheimer Research | Year: 2010

Dimebon, originally developed as an anti-histamine drug, is being re-purposed for new indications as an effective treatment for patients suffering from Alzheimer's and Huntington's diseases, albeit with an as-yet unknown mechanism of action. We have performed molecular pharmacology profiling of this drug on a panel of 70 targets to characterize the spectrum of its activity, with the goal to possibly elucidate a potential molecular mechanism for the re-purposing of this drug candidate. We show that in addition to histaminergic receptors, Dimebon exhibits high affinity to a constellation of other receptors; specifically serotonergic, alpha-adrenergic and dopaminergic receptors. Good correlations with published literature were obtained for the affinity of Dimebon to inhibit butyrylcholinesterase, interact with H1and H2 receptors (Ki = 2 nM and 232 nM), and to block histamine-induced calcium fluxes in cells. Within serotonergic receptor subtypes, Dimebon shows highest affinity for 5-HT7 (Ki=8 nM) and 5-HT6 (Ki=34 nM) receptors, with the relative affinity rank-order of 5-HT7 > 5-HT6 ≥ 5-HT2A = 5-HT2C > 5-HT1A = 5-HT1B > 5-HT2B=5-HT3. Dimebon also interacts with adrenergic receptor subtypes (rank-order: α1A (Ki = 55 nM)= α1B ≥ α2A (Ki = 120 nM) = α1D), and dopaminergic receptor subtypes (rank-order: D1=D2S=D2L (Ki ̃ 600 nM) >D3??D4.2>D4.4??D4.7). These results demonstrate a molecular pharmacological basis for re-purposing of this drug to new therapeutic areas. The informed targeting of the combined molecular target activities may provide additional advantages for patients suffering from similar diseases syndromes. Understanding the role that different pathways play in diseases with complex etiologies may allow for the rational design of multi-target drugs. © 2010 Bentham Science Publishers Ltd. Source


Fang S.,Salk Institute for Biological Studies | Suh J.M.,Salk Institute for Biological Studies | Reilly S.M.,University of Michigan | Yu E.,Salk Institute for Biological Studies | And 18 more authors.
Nature Medicine | Year: 2015

The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome. Source


Preskorn S.H.,University of Kansas | Gawryl M.,EnVivo Pharmaceuticals Inc. | Dgetluck N.,EnVivo Pharmaceuticals Inc. | Palfreyman M.,ChemDiv Inc. | And 2 more authors.
Journal of Psychiatric Practice | Year: 2014

Cognitive impairment is a cause of significant disability in patients with schizophrenia. To date, no drug has been approved for this indication by the U.S. Food and Drug Administration. This article presents findings suggesting that a medication targeting the alpha-7 nicotinic acetylcholine receptor (α7 nAChR) might meet this need. This single-center, randomized, parallel-group, double-blind,placebo-controlled study examined 21 medically stable patients with schizophrenia or schizoaffective disorder treated with second generation antipsychotics. Patients were treated with a daily dose of either 0.3 mg (n=8) or 1.0 mg (n=9) of EVP-6124, an α7 nAChR partial agonist, or placebo (n=4). Treatment continued for 21 days while patients continued their usual antipsychotic medication: aripiprazole (10-30 mg/day), olanzapine (10-20 mg/day), paliperidone (3-12 mg/day), or risperidone (2-16 mg/day). Cognitive test performance, eventrelated electroencephalographic (EEG) potentials, clinical symptoms, laboratory values, and clinical side effects were measured. EVP-6124 was well tolerated and showed positive, and in some cases, dose-dependent effects on several EEG responses, especially the Mismatch Negativity and P300 potentials. Positive effects were also found in performance on cognitive tests that measured non-verbal learning, memory, and executive function. This study is an example of the type of early proof of concept trial that is done to enable drug developers to evaluate whether to continue research on an agent. Based on the promising findings in this study, larger phase II studies were initiated to further test the pro-cognitive effects of EVP-6124 in patients with chronic schizophrenia.Clinical Trials Registration: Safety, Tolerability, and Pharmacokinetic Study of EVP-6124 in Patients with Schizophrenia, NCT01556763 http://clinicaltrials.gov/ct2/show/NCT01556763?term= NCT01556763&rank=1 (Journal of Psychiatric Practice 2014;20:12-24) Copyright © 2014 Lippincott Williams & Wilkins Inc. Source


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2007

DESCRIPTION (provided by applicant): Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism required for the addition of CO2 to acetyl-CoA to make malonyl-CoA. In mammals, malonyl-CoA serves as a precursor for the synthesis of fatty acids but it also regulates fatty acid oxidation in mitochondria. There are two ACC isozymes in humans, with very similar amino acid sequences, differing mainly by a 200-residue N-terminal extension on ACC2 that directs this form of the enzyme to mitochondria. There, ACC2-catalyzed synthesis of malonyl- CoA leads to suppression of fatty acid transport and subsequent oxidation. ACC1- synthesized malonyl-CoA is used for fatty acid synthesis. We propose to screen a small- molecule library to find novel inhibitors of ACC2 as lead compounds for the development of new pharmacotherapies to treat obesity. We have constructed yeast gene- replacement strains depending for growth on either human ACC. Our research has already shown that growth of such ACC gene-replacement strains is inhibited by compounds targeting foreign ACCs. We have developed and tested a high throughput protocol necessary to screen large chemical libraries. We also propose to conduct follow-up experiments to determine the specificity of any new inhibitor identified in the screen, using our collection of yeast gene-replacement strains carrying different ACCs, and to confirm ACC as their target, using enzymatic assays. Obesity is a common and prevalent nutritional disorder linked to significant morbidity and premature mortality caused by other serious medical conditions such as diabetes and coronary disease. Acetyl-CoA carboxylase, a key lipid metabolic enzyme, is being investigated as a potential target for new pharmacotherapies to treat the disorder. New medications based on small-molecule inhibitors of the enzyme acting by increasing fatty acid degradation by oxidation or decreasing fatty acid synthesis could become new urgently needed tools to combat the disease.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase II | Award Amount: 750.09K | Year: 2006

DESCRIPTION (provided by applicant): Development of drugs based on the MC2R antagonists will directly benefit children with CAH and Cushing's diseases, and will help us to understand MC2R's role in metabolic pathways. The long term goal of this project is to discover small molecule inhibitors of MC2 receptor and develop drug to treat several metabolic diseases including CAH and Cushing's diseases afflicting children. Our Phase I studies to identify novel ACTH small molecule antagonists were successful; we were able to identified three novel non-peptide small molecule ACTH antagonists that have high affinity to the MC2R. The inhibitors belong to the same chemotype with a similar chemical backbone. These compounds are full ACTH antagonists that potently inhibit ACTH-stimulated adrenal cell activity. We have achieved the Phase I goals and discovered a novel series of small molecule non-peptide ACTH antagonists. Phase II of this project will be dedicated to extending our studies of ACTH antagonists by examining structure-activity relationships using series analogs of identified inhibitors to assess their ACTH antagonist potency, specificity, and selectivity, and initiating animal testing. Specifically we will: 1) examine ACTH antagonist structure-activity relationships to increase our understanding of basic structural requirements for the compound to bind to MC2R; 2) assess selectivity and specificity of the ACTH antagonists to other melanocortin and unrelated receptors; (3) assess ADME- related characteristics such as human serum albumin binding, P450 inhibition, lipid membrane, CACO-2 permeability, and in vitro cytotoxicity; 4) perform in vivo animal toxicology/pharmacokinetic testing; and 5) assess ability to block ACTH action in an in vivo animal model. These studies combine ChemDiv's expertise in drug discovery with a Yale laboratory with expertise in GPCR action and treatment of adrenal disorders. The studies will lead to novel approaches for treating patients with ACTH-dependent adrenal disorders. Project Narrative: The production of adrenal gland hormones, including cortisol and androgens, is regulated by pituitary ACTH (adrenocorticotropin hormone), which acts via the melanocortin-2 receptor (MC2R) to stimulate steroid production. Serious clinical disorders affecting the adrenal gland include congenital virilizing adrenal hyperplasia (CAH) and Cushing's disease. The ability to antagonize ACTH action will greatly facilitate the care of these and other conditions affecting the adrenal gland. Unfortunately, high-affinity small molecule ACTH antagonists are not identified yet and are not currently available for clinical use.

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