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Ivachtchenko A.V.,ChemDiv Inc. | Ivachtchenko A.V.,RAS Institute of Organic Chemistry | Ivanenkov Y.A.,RAS Institute of Chemistry | Tkachenko S.E.,RAS Institute of Organic Chemistry
Expert Opinion on Therapeutic Patents | Year: 2010

Importance of the field: Among the GPCR subclasses that have been discovered to date, 5-HT receptors are especially attractive as key biological targets with enormous clinical importance. In particular, during the last decade, the 5-HT6 receptor has gained increasing attention due to extensive cellular functions. It has also been suggested that its activity can be mediated by inverse agonists. Areas covered in this review: Summarizing the points listed above, the current review primarily focuses on patent literature within the title field, evolution and trends that have not yet been covered in such depth in other published papers. What the reader will gain: To obtain a clear understanding of the situation and dynamics within the field of 5-HT6 ligands, having an obvious pharmaceutical potential in terms of related patents, we provide a comprehensive search through several key patent collections. We have covered promising small molecule compounds which are being evaluated in different clinical trials as well as drugs currently available in the pharmaceutical market. In addition, readers will gain a deep insight into the patent specification, geographic distribution, tendency and patent holders presented. Take home message: Several of 5-HT6-targeted compounds are reasonably regarded as powerful drug candidates for the treatment of a range of neuropathological disorders, including Alzheimer's disease and Huntington's disease. © 2010 Informa UK, Ltd.


Ivachtchenko A.V.,ChemDiv Inc. | Ivanenkov Y.A.,ChemDiv Inc. | Ivanenkov Y.A.,Moscow Institute of Physics and Technology
Current Bioactive Compounds | Year: 2013

In recent years, considerable research efforts have focused on the role of serotonin in various pathological states, as well as on the identification of the respective serotonin receptors involved. Among serotonin receptors, 5-HT6 is the most recently discovered sub-class. Despite the development of multiple selective ligands, the functional role of this receptor has thus far remained elusive. Available in vitro and in vivo evidence indicates that 5-HT6 receptor antagonists can produce promnesic or antiamnesic effects in a variety of contexts, including memory formation, age-related cognitive impairments, and memory deficits associated with conditions such as schizophrenia, Parkinson's disease, and Alzheimer's disease. Recent progress in the understanding of the 5-HT6 receptor and its ligands includes a suggested constitutive activity for the receptor, development of a number of multimodal small molecule ligands, and re-classification of many selective antagonists as pseudo-selective compounds. In light of these findings, the observed pharmacological effects produced by 5-HT6 ligands are now properly assigned to a spectrum of related biological targets, rather than to an individual receptor © 2013 Bentham Science Publishers.


Ivachtchenko A.V.,ChemDiv Inc. | Ivachtchenko A.V.,RAS Institute of Chemistry | Ivanenkov Y.A.,ChemDiv Inc. | Ivanenkov Y.A.,RAS Institute of Chemistry | Skorenko A.V.,RAS Institute of Chemistry
Expert Opinion on Therapeutic Patents | Year: 2012

Introduction: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5-HT receptors (5-HT6Rs) are highly attractive as important biological targets with enormous clinical importance. Among this sub-class, 5-HT6R is the most recently discovered group. Available biological data clearly indicate that 5-HT6R antagonists can be used as effective regulators in a variety of contexts, including memory formation, age-related cognitive impairments and memory deficits associated with conditions such as schizophrenia, Parkinson's disease (PD) and Alzheimer's disease (AD). Therefore, this receptor has already attracted a considerable attention within the scientific community, due to its versatile therapeutic potential. Areas covered: The current paper is an update to the comprehensive review article published previously in Expert Opinion on Therapeutic Patents [1] Ivashchenko AV, Ivanenkov YA, Tkachenko SE. 5-Hydroxytryptamine subtype 6 receptor modulators: a patent survey. Expert Opin. Ther. Pat, 2010, 20, 1171-1196. Here, the authors mainly focus on small-molecule compounds 5-HT6 antagonists which have been described in recent patent literature, since the end of 2009. To obtain a clear understanding of the situation and dynamic development within the field of 5-HT6 ligands, having an obvious pharmaceutical potential in terms of related patents, the authors provide a comprehensive search through several key patent collections. They describe the reported heterocyclic compounds with no sulfonyl moiety in sufficient detail to provide a valuable insight in the 5-HT6R chemistry and pharmacology. Most of the described compounds are currently classified as multimodal agents with high affinity toward 5-HT6R. Expert opinion: Recent progress in the understanding of the 5-HT6 receptor function and structure includes a suggested constitutive activity for the receptor, development of a number of multimodal small-molecule ligands and re-classification of many selective antagonists as pseudo-selective agents. Several heterocylic structures with or without any basic center provide sufficient supramolecular interactions and show high agonistic/antagonistic activity against 5-HT6R. Many 'multitarget' drugs acting, for instance, against several isoforms of 5-HTR, including 5-HT6R subtype, as well as against dopamine and/or histamine receptors were shown to have beneficial therapeutic effects. At the same time, these 'unselective' compounds may also increase the side-effect potential. The ensemble of antagonistic activity against 5-HT6R and inhibition potency against BuChE can be regarded as the most promising basis for the development of effective drugs with a sufficient therapeutic window for the treatment of several neurodegenerative diseases, including AD and PD. © 2012 Informa UK, Ltd.


Ivachtchenko A.V.,ChemDiv Inc. | Ivachtchenko A.V.,RAS Institute of Organic Chemistry | Ivanenkov Y.A.,ChemDiv Inc. | Ivanenkov Y.A.,RAS Institute of Chemistry
Expert Opinion on Therapeutic Patents | Year: 2012

Introduction: Among a variety of proteins included in a relatively wide GPCR family, serotonin 5HT receptors (5HT6Rs) are highly attractive as important biological targets with enormous clinical importance. Among this subclass, 5HT6R is the most recently discovered group. Available biological data clearly indicate that 5HT6R antagonists can be used as effective regulators in a variety of contexts, including memory formation, age-related cognitive impairments and memory deficits associated with conditions such as schizophrenia, Parkinson's disease and Alzheimer's disease. Therefore, this receptor has already attracted a considerable attention within the scientific community, due to its versatile therapeutic potential. Areas covered: The current paper is an update to the comprehensive review article published previously in Expert Opinion on Therapeutic Patents (see issue 20(7), 2010). Here, the main focus is on small-molecule compounds 5HT6 antagonists which have been described in recent patent literature, since the end of 2009. To obtain a clear understanding of the situation and dynamic within the field of 5HT6 ligands, having an obvious pharmaceutical potential in terms of related patents, a comprehensive search through several key patent collections have been provided. The authors describe the reported chemical classes and scaffolds in sufficient detail to provide a valuable insight in the 5HT6R chemistry and pharmacology. The review consists of two core parts with separate sections arranged in accordance with the main structural features of 5HT6R ligands. Expert opinion: Recent progress in the understanding of the 5HT6 receptor function and structure includes a suggested constitutive activity for the receptor, development of a number of multimodal small molecule ligands and re-classification of many selective antagonists as pseudo-selective agents. Heterocycles with sulfonyl group and without any basic center provide sufficient supramolecular interactions and show high antagonistic activity against 5HT6R. © 2012 Informa UK, Ltd.


Ivanenkov Y.A.,ChemDiv Inc. | Ivanenkov Y.A.,Russian Academy of Sciences | Balakin K.V.,Russian Academy of Sciences | Lavrovsky Y.,ChemDiv Inc.
Mini-Reviews in Medicinal Chemistry | Year: 2011

In the current review, we discuss the role of NF-kB and JAK/STAT signaling pathways and their small molecule regulators in the therapy of inflammatory diseases. Considering potential harmful effects directly assigned to the COX-2 inhibition, novel therapeutically-relevant biological targets such as NF-kB and JAK/STAT signaling pathways have received a growing attention. Here we summarize recent progress in the identification and development of novel, clinically approved or evaluated small molecule regulators of these signaling cascades as promising anti-inflammatory therapeutics. In addition, we illustrate key structural modifications and bioisosteric transformations among these inhibitors to provide a helpful basis for further development of novel small molecule anti-inflammatory agents. © 2011 Bentham Science Publishers Ltd.


Ivachtchenko A.V.,RAS Institute of Organic Chemistry | Golovina E.S.,Chemical Diversity Research Institute | Kadieva M.G.,RAS Institute of Organic Chemistry | Kysil V.M.,ChemDiv Inc. | And 3 more authors.
Journal of Medicinal Chemistry | Year: 2011

Syntheses, biological evaluation as 5-HT 6 receptor (5-HT 6R) antagonists, and structure-activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT 6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT 6R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT 6R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor. © 2011 American Chemical Society.


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.


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.


Burley S.D.,San Diego State University | Lam V.V.,ChemDiv Inc. | Lakner F.J.,ChemDiv Inc. | Bergdahl B.M.,San Diego State University | Parker M.A.,San Diego State University
Organic Letters | Year: 2013

A new route to the ergoline skeleton has been developed that does not require prior functionalization of the indole 4-position. The indole nucleus is introduced late in the synthesis to allow for eventual efficient introduction of substituents in this region. Key steps include Negishi coupling of a three-carbon chain to a bromonicotinate ester, Fischer indole synthesis to facilitate incorporation of substituents via phenylhydrazines, and Pd-catalyzed cyclization to form the ergoline C ring. © 2013 American Chemical Society.


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.

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