Chemical Diversity Research Institute

San Diego, United States

Chemical Diversity Research Institute

San Diego, United States
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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.


Chigorina E.A.,Chemical Diversity Research Institute
Chemistry of Heterocyclic Compounds | Year: 2013

1-(Cyanoacetyl)-3,5-dimethylpyrazole reacted with 2-cyanoacrylamides in the presence of triethylamine with the formation of triethylammonium salts of 4-monosubstituted-2,6-dioxopiperidine-3,5-di-carbonitriles (Guareschi imides) or the products of their oxidation, the 4-aryl-3,5-dicyano-6-oxo-1,6-di- hydropyridin-2-olates. © 2013 Springer Science+Business Media New York.


Chigorina E.A.,Chemical Diversity Research Institute
Synlett | Year: 2014

A Synthesis of Biologically Active Amides The reaction of 1 with various amine substrates was successful for the synthesis of biologically active compounds. Thus, imino-2Hchromen- 3-carboxamide derivatives 4, inhibitors of β-secretase, were obtained in three steps starting from substituted anilines and pyrazole 1. The reaction of spirocyclic amine 5 with a two-fold excess of 1 led to N-cyanoacetyl derivative 6, an inhibitor of Janus kinase 3. (B) Synthesis of Oxadiazoles New 5-cyanomethyl-1,2,4-oxadiazoles 7 have been synthesized by the reaction of pyrazole 1 with arylamidoximes. The obtained compounds 7 are recognized as valuable building blocks for heterocyclic synthesis. (C) Synthesis of Guareschi Imides Pyrazole 1 can be used as an active methylene compound capable of successfully replacing ethyl cyanoacetate in most cases. Thus, the Guareschi condensation could be vastly improved by replacing ethyl cyanoacetate with 1. The Guareschi imides as well as their sulfur and selenium analogues were obtained as triethylammonium salts 8 by a Michael-type addition of 1 to 2-cyanoacrylamides 9 followed by subsequent cyclocondensation. (D) O- and C-Cyanoacetylation While a number of papers have focused on the reactions of 1 with various N-nucleophiles, the reactions of cyanoacetylpyrazole with C- and O-nucleophiles have been neglected. The only examples of such reactions were reported by Swellem et al.15 and Tverdokhlebov and co-workers.16 Ternary condensation of 2-nitrobenzaldehyde with pyrazole 1 and ethylene glycol or glycerol gives 2-cyanoacrylates 10 in about 40% yield.15 Despite the low yields, this approach is the method of choice in cases where the corresponding cyanoacetates are not readily available. The first examples of C-cyanoacetylation with 1 were reported a few years ago. The hetarylideneacetonitrile 11 reacts with 1 to give β-keto glutaronitrile 12. The latter upon treatment with HBr readily cyclizes to pyridine 13 in good yield. (E) Azo Coupling and Related Reactions As an active methylene compound, 1 readily reacts with diazonium salts to afford hydrazone products 14, which were found to be good starting materials for the synthesis of a variety of functionalized heterocycles. 17 In a similar manner, 1 gives dimethylaminomethylene derivative 15 upon treatment with DMF dimethyl acetal. (F) Functionalized Phosphorus Ylides The highly functionalized phosphorus ylides 16 are accessible in high yield by a three-component reaction of triphenylphosphine, dialkyl acetylene-dicarboxylates, and pyrazole 1. © Georg Thieme Verlag Stuttgart. New York.


Kulebyakin K.,Moscow State University | Karpova L.,Moscow State University | Lakonsteva E.,Chemical Diversity Research Institute | Krasavin M.,Chemical Diversity Research Institute | Boldyrev A.,Moscow State University
Amino Acids | Year: 2012

Carnosine is a known protector of neuronal cells against oxidative injury which prevents both apoptotic and necrotic cellular death. It was shown earlier that carnosine serves as an intracellular buffer of free radicals. Using the model of ligand-dependent oxidative stress in neurons, we have shown that homocysteine (HC) initiates long-term activation of extracellular signal regulated kinase, isoforms 1 and 2 (ERK 1/2) and Jun N-terminal kinase (JNK) which corresponds to exitotoxic effect resulting in cellular death. l-Carnosine (β-alanyl-l-histidine) protects neurons from both excitotoxic effect of homocysteine and cellular death. Its analogs, β-alanyl-d-histidine (d-carnosine) and l-histidyl-β-alanine, restricted accumulation of free radicals and delayed activation of ERK1/2 and JNK in neuronal cells, but did not promote neuronal viability. © 2011 Springer-Verlag.


Krasavin M.,Yaroslavl State Pedagogical University | Bushkova E.,Yaroslavl State Pedagogical University | Parchinsky V.,Chemical Diversity Research Institute | Shumsky A.,Chemical Diversity Research Institute
Synthesis | Year: 2010

A number of Nα-alkyl,Nβ-acylhydrazines have been synthesized via the Ugi reaction of N-acylhydrazones with an isocyanide and trifluoroacetic acid. The trifluoroacetic acid acted as a silent partner and becomes removed upon basic workup of the reaction. These compounds have been efficiently modified further via reductive alkylation to produce Nα,Nα-dialkyl,Nβ- acylhydrazines. The two groups of novel hydrazinopeptide motifs have been shown by simple 1H NMR spectroscopic experiments to display two different secondary structure patterns. These observations were confirmed by X-ray crystallographic analysis. Combining the hydrazone and carboxylic acid moieties in one reaction precursor offers the opportunity for an intramolecular hydrazino-Ugi reaction, which was also demonstrated. © Georg Thieme Verlag Stuttgart • New York.


Krasavin M.,Yaroslavl State Pedagogical University | Parchinsky V.,Chemical Diversity Research Institute
Tetrahedron Letters | Year: 2010

A novel approach to skeletally diverse 3-oxoisoindolines has been developed which includes preparation of Ugi adducts containing thiophene and fumaric acid residues. When treated with excess m-CPBA at room temperature, these precursors undergo a simple oxidative cycloaddition/aromatization transformation and the corresponding 3-oxoisoindoline products are isolated in fair chemical yield over two steps. The second step is thought to include S-oxidation/IMDA/S-oxidation/ SO2 extrusion/aromatization events. © 2010 Elsevier Ltd. All rights reserved.


Krasavin M.,Yaroslavl State Pedagogical University | Parchinsky V.,Chemical Diversity Research Institute | Shumsky A.,Chemical Diversity Research Institute | Konstantinov I.,Chemical Diversity Research Institute | Vantskul A.,Chemical Diversity Research Institute
Tetrahedron Letters | Year: 2010

A four-center, three-component Ugi-type reaction of a variety of keto acids, Boc- or Cbz-protected hydrazine, and isocyanides offers a simple and high yielding access to cyclic products containing an N-aminolactam unit. The latter are shown to form consistently an intramolecular hydrogen bond leading to a β-turn-like secondary structure. The possibility of integrating such N-aminolactam units (without disruption of the folded structure) into pseudotripeptide fragments is demonstrated. © 2010 Elsevier Ltd. All rights reserved.


Parchinsky V.,Chemical Diversity Research Institute | Shumsky A.,Chemical Diversity Research Institute | Krasavin M.,Griffith University
Tetrahedron Letters | Year: 2011

A facile and operationally simple route to diastereomerically pure, natural-like 3-azabicyclo[3.3.1]non-6-enes via microwave-assisted, BF 3·OEt2-promoted aza-Prins reaction has been developed. Complexity-generating transformations based on these products involving reactive functionalities introduced during the aza-Prins step have been developed. © 2011 Elsevier B.V. All rights reserved.


Parchinsky V.,Chemical Diversity Research Institute | Shumsky A.,Chemical Diversity Research Institute | Krasavin M.,Griffith University
Tetrahedron Letters | Year: 2011

Novel symmetrically and unsymmetrically disubstituted 1-azaadamantanes were prepared as a single, chiral diastereomer via double microwave-assisted aza-Prins cyclization in one-pot or sequential reaction format. © 2011 Elsevier B.V. All rights reserved.

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