ChemDiv Inc.

San Diego, CA, United States

ChemDiv Inc.

San Diego, CA, United States
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Ivachtchenko A.V.,Alla Chemical LLC | Ivachtchenko A.V.,Avineuro Pharmaceuticals Inc. | Ivanenkov Y.A.,Moscow Institute of Physics and Technology | Veselov M.S.,Moscow Institute of Physics and Technology | Okun I.M.,ChemDiv Inc.
Current Alzheimer Research | Year: 2017

Background: In recent years, 5-hydroxytryptamine subtype 6 receptor (5-HT6 receptor, 5- HT6R) has emerged as a promising therapeutic target for the treatment of neuropathological disorders, including Alzheimer’s disease (AD) and schizophrenia. 5-HT6 receptors were hypothesized to be implicated in the processes of learning, memory, and cognition with 5-HT6R antagonists being effective in animal models of cognition and memory impairment. Several selective 5-HT6R ligands are currently undergoing clinical trials for treatment of AD. Methods: We describe results of preclinical development of a novel and highly selective and potent 5- HT6R antagonist, AVN-322, as a clinical candidate for the treatment of AD to improve concurrent debilitation of memory and cognition in the AD patients, and schizophrenia as a substance with antipsychotic effect. In the manuscript, we present its in vitro and vivo efficacy, ADME, pharmacokinetics in animals and in humans, and toxicity. Results: While having high binding affinity in medium picomolar range, the lead compound demonstrates substantially better selectivity index then the reference drug candidates currently being tested in clinical studies. AVN-322 showed high oral bioavailability and favorable blood-brain barrier (BBB) penetration. In vivo testing revealed its clear cognition enhancing effect. AVN-322 significantly restored both scopolamine- and MK-801-induced cognitive dysfunction and demonstrated antipsychotic potential. Conclusion: Taking into account its good safety profile and favorable pharmacokinetics, AVN-322 can be reasonably considered as a novel drug candidate for the treatment of neurological disorders such as AD and/or schizophrenia. © 2017 Bentham Science Publishers.

Strand M.F.,University of Oslo | Wilson S.R.,University of Oslo | Dembinski J.L.,University of Oslo | Holsworth D.D.,ChemDiv Inc. | And 4 more authors.
PLoS ONE | Year: 2011

Background: Hedgehog (Hh) signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO) receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials. Principal Findings: Using Shh-Light II (Shh-L2) and alkaline phosphatase (AP) based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)benzamide). MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU) in the low μM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo. Significance: We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists. © 2011 Strand et al.

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.

Ivachtchenko A.V.,ChemDiv Inc. | Golovina E.S.,Chemical Diversity Research Institute | Kadieva M.G.,Chemical Diversity Research Institute | Kysil V.M.,ChemDiv Inc. | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Synthesis and biological evaluation of a new series of structurally unrestricted and intramolecular hydrogen bond restricted derivatives of 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines (angular tricyclics) and 3-(phenylsulfonyl)pyrazolo[1,5-a]pyrido[4,3-d]pyrimidines (linear tricyclics) are described. Structurally restricted derivatives are highly potent and selective blockers of 5-HT 6 receptors with little difference between angular or linear shape of the tricyclic core, the angular species being only slightly more potent. The angular representative of 3-(phenylsulfonyl) pyrazolo[1,5-a]pyrido[3,4-e]pyrimidines, 5, can be considered as more favorable candidate for further development as it shows only weak 5-HT 2B blocking activity (IC 50 = 6.16 μM as compared with IC 50 = 1.8 nM for 5-HT 6 receptors) and very low hERG potassium channel blocking potency (IC 50 = 54.2 μM). The linear analog, 11, is less favorable as while showing no binding to the 5-HT 2B receptor at concentrations of up to 10 μM, it exhibits quite a high potency to block the hERG channel (IC 50 = 0.5 μM). © 2012 Elsevier Ltd. All rights reserved.

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 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.

Ivachtchenko A.V.,ChemDiv Inc. | Ivanenkov Y.A.,ChemDiv Inc. | Kysil V.M.,ChemDiv Inc. | Yu Krasavin M.,ChemDiv Inc. | Ilyin A.P.,ChemDiv Inc.
Russian Chemical Reviews | Year: 2010

The latest achievements in the field of isocyanide-based multicomponent reactions for the synthesis of heterocycles are generalized. The attention is focused on the intramolecular Ugi reactions of oxocarboxylic acids and the reactions of diaza nucleophiles developed in recent years. The data on the biological activities of the products are presented and the advantages of this method as a convenient and effective tool of medicinal chemistry are demonstrated. The bibliography includes 162 references. © 2010 Russian Academy of Sciences and Turpion Ltd.

ChemDiv Inc. | Date: 2011-11-22

Chemical reagents for non-medical purposes; Reagent for chemical analyses; Reagents for use in scientific apparatus for chemical or biological analysis; Chemical preparations for scientific purposes, namely, products with the main purpose to provide time- and cost-efficient chemical solutions for discovery research, namely, characterizing pharmacological properties of prototype molecules. Custom production of compounds with defined physico-chemical properties for others; scale-ups, namely, contract manufacturing production of clinical testing and commercial supplies of active pharmaceutical ingredients and finished drug dosage forms. Analysis of the mode of action of chemical combinations on animals; Chemical analysis; Chemical laboratories; Chemical research; Chemical, biochemical, biological and bacteriological research and analysis; Development and test of chemical production methods; Development of pharmaceutical preparations and medicines; Pharmaceutical drug development services; Pharmaceutical research and development; Pharmaceutical research services; Research and development for new products for others; Research on the subject of pharmaceuticals; Scientific research and development; Scientific research services with the main purpose to provide time- and cost-efficient chemical solutions for discovery research, namely, characterizing pharmacological properties of prototype molecules; Scientific research and development of new synthetic approaches to production of new chemical entities; scientific research and development in the field of expanding existing chemical libraries to meet desirable goals; working on and evaluation of chemical syntheses, namely, characterizing pharmacological properties of molecules chemically related to known active drug compounds.

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