- Synthesis and biological assessment of 4,1-benzothiazepines with neuroprotective activity on the Ca2+ overload for the treatment of neurodegenerative diseases and stroke
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In excitable cells, mitochondria play a key role in the regulation of the cytosolic Ca2+ levels. A dysregulation of the mitochondrial Ca2+ buffering machinery derives in serious pathologies, where neurodegenerative diseases highlight. Since the mitochondrial Na+/Ca2+ exchanger (NCLX) is the principal efflux pathway of Ca2+ to the cytosol, drugs capable of blocking NCLX have been proposed to act as neuroprotectants in neuronal damage scenarios exacerbated by Ca2+ overload. In our search of optimized NCLX blockers with augmented drug-likeness, we herein describe the synthesis and pharmacological characterization of new benzothiazepines analogues to the first-in-class NCLX blocker CGP37157 and its further derivative ITH12575, synthesized by our research group. As a result, we found two new compounds with an increased neuroprotective activity, neuronal Ca2+ regulatory activity and improved drug-likeness and pharmacokinetic properties, such as clog p or brain permeability, measured by PAMPA experiments.
- Arribas, Raquel L.,Braun-Cornejo, María,De Los Ríos, Cristóbal,Estrada-Valencia, Martín,Moreno-Castro, Manuel,Pérez-Marín, Raquel,Rubio-Alarcón, Marcos,Viejo, Lucía
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- One-pot homo- and cross-coupling of diazanaphthalenes via C-H substitution: Synthesis of Bis- and Tris-diazanaphthalenes
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The transition metal-free coupling reactions of unactivated diazanaphthalenes were studied using only lithium tetramethylpiperidine (LiTMP) reagent. Symmetrical and nonsymmetrical bis-diazanaphthalenes were synthesized in moderate to high yield by homo- and cross-coupling of related monomers. In addition, the single-step synthesis of diquinoxalino [2,3-a: 2', 3'c] phenazine and 2,2': 3', 2″ - terquinoxaline using the appropriate equivalent amount of LiTMP was performed. The products were characterized by means of NMR spectroscopy and HRMS spectrometry.
- Ucar, Sefa,Dastan, Arif
-
supporting information
p. 4013 - 4022
(2020/09/21)
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- Design, Synthesis, and Biological Evaluation of 4-Quinoline Carboxylic Acids as Inhibitors of Dihydroorotate Dehydrogenase
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We pursued a structure-guided approach toward the development of improved dihydroorotate dehydrogenase (DHODH) inhibitors with the goal of forming new interactions between DHODH and the brequinar class of inhibitors. Two potential residues, T63 and Y356, suitable for novel H-bonding interactions, were identified in the brequinar-binding pocket. Analogues were designed to maintain the essential pharmacophore and form new electrostatic interactions through strategically positioned H-bond accepting groups. This effort led to the discovery of potent quinoline-based analogues 41 (DHODH IC50 = 9.71 ± 1.4 nM) and 43 (DHODH IC50 = 26.2 ± 1.8 nM). A cocrystal structure between 43 and DHODH depicts a novel water mediated H-bond interaction with T63. Additional optimization led to the 1,7-naphthyridine 46 (DHODH IC50 = 28.3 ± 3.3 nM) that forms a novel H-bond with Y356. Importantly, compound 41 possesses significant oral bioavailability (F = 56%) and an elimination t1/2 = 2.78 h (PO dosing). In conclusion, the data supports further preclinical studies of our lead compounds toward selection of a candidate for early-stage clinical development.
- Madak, Joseph T.,Cuthbertson, Christine R.,Miyata, Yoshinari,Tamura, Shuzo,Petrunak, Elyse M.,Stuckey, Jeanne A.,Han, Yanyan,He, Miao,Sun, Duxin,Showalter, Hollis D.,Neamati, Nouri
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p. 5162 - 5186
(2018/05/15)
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- Amine Activation: Synthesis of N-(Hetero)arylamides from Isothioureas and Carboxylic Acids
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A novel method for N-(hetero)arylamide synthesis based on rarely explored amine activation, rather than classical acid activation, is reported. The activated amines are easily prepared using a three-component reaction with commercial reagents. The new method shows a broad scope including challenging amides not (efficiently) accessible via classical protocols.
- Zhu, Yan-Ping,Sergeyev, Sergey,Franck, Philippe,Orru, Romano V. A.,Maes, Bert U. W.
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supporting information
p. 4602 - 4605
(2016/09/28)
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- Fragment-Based Discovery of Dual JC Virus and BK Virus Helicase Inhibitors
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There are currently no treatments for life-threatening infections caused by human polyomaviruses JCV and BKV. We therefore report herein the first crystal structure of the hexameric helicase of JCV large T antigen (apo) and its use to drive the structure-based design of dual JCV and BKV ATP-competitive inhibitors. The crystal structures obtained by soaking our early inhibitors into the JCV helicase allowed us to rapidly improve the biochemical activity of our inhibitors from 18 μM for the early 6-(2-methoxyphenyl)- and the 6-(2-ethoxyphenyl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole hits 1a and 1b to 0.6 μM for triazolopyridine 12i. In addition, we were able to demonstrate measurable antiviral activity in Vero cells for our thiazolopyridine series in the absence of marked cytotoxicity, thus confirming the usefulness of this approach.
- Bonafoux, Dominique,Nanthakumar, Suganthini,Bandarage, Upul K.,Memmott, Christine,Lowe, Derek,Aronov, Alex M.,Bhisetti, Govinda Rao,Bonanno, Kenneth C.,Coll, Joyce,Leeman, Joshua,Lepre, Christopher A.,Lu, Fan,Perola, Emanuele,Rijnbrand, Rene,Taylor, William P.,Wilson, Dean,Zhou, Yi,Zwahlen, Jacque,Ter Haar, Ernst
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p. 7138 - 7151
(2016/08/24)
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- METALLOENZYME INHIBITOR COMPOUNDS
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The instant invention describes compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.
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Page/Page column 88-89
(2014/08/07)
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- PROTEIN KINASE INHIBITORS
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The present invention provides a compound incorporating a group of formula (I) wherein: 1 of X, Y and Z is nitrogen and the other 2 are carbon; V is sulpur or carbon; R3 is oxygen or fluorine; R4 is an optionally present C1-3 alkyl group optionally substituted by fluorine; R5 is an optionally present cyclic group with 5-7 heavy atoms in the ring which may be carbocyclic or heterocyclic and aromatic or aliphatic and is optionally substituted, e.g. by a halogen, C1-2 alkyl or fluoroalkyl, OH, OR6, cyano, COOR6, CONHR6, sulfonamide or NHR6, in which R6 is a C1-2 alkyl or fluoroalkyl; at least one of R4 and R5 is present and R4 and R5 may both be present; m and n are each 1 or 2 depending on the identity of V and R3; when n=2 each R3 may be the same or different but are preferably the same, when m=2, each R4 and each R5 may be the same or different but are preferably the same; and W represents hydrogen, carbon, nitrogen, oxygen or sulphur; or incorporating a salt, hydrate or solvate of a group of formula (I); as well as therapeutic uses of these compounds, in particular as inhibitors of protein kinase activity and in the treatment of inflammation, inflammatory conditions and cancer.
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Page/Page column 17; 18
(2015/01/09)
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- COMPOUNDS
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The present invention provides a compound incorporating a group of formula (I) wherein: 1 of X, Y and Z is nitrogen and the other 2 are carbon; R" is hydrogen, methyl, ethyl or propyl; and W represents hydrogen, carbon, nitrogen, oxygen or sulphur; or incorporating a salt, hydrate or solvate of a group of formula (I); as well as therapeutic uses of these compounds, in particular as inhibitors of protein kinase activity and in the treatment of inflammation, inflammatory conditions and cancer.
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Page/Page column 16; 17
(2015/01/09)
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- ANTIBACTERIAL AGENTS
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Antibacterial compounds of formula (I) are provided, as well as stereoisomers and pharmaceutically acceptable salts thereof; pharmaceutical compositions comprising such compounds; methods of treating bacterial infections by the administration of such compounds; and processes for the preparation of such compounds.
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Page/Page column 88
(2013/12/03)
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- Annelated pyridines as highly nucleophilic and Lewis basic catalysts for acylation reactions
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New heterocyclic derivatives of 9-azajulolidine have been synthesized and characterized with respect to their nucleophilicity and Lewis basicity. The Lewis basicity of these bases as quantified through their theoretically calculated methyl-cation affinities correlate well with the experimentally measured reaction rates for addition to benzhydryl cations. All newly synthesized pyridines show exceptional catalytic activities in benchmark acylation reactions, which correlate only poorly with Lewis basicity or nucleophilicity parameters. A combination of Lewis basicity with charge and geometric parameters in the framework of a three-component quantitative structure-activity relationship (QSAR) model is, however, highly predictive. Copyright
- Tandon, Raman,Unzner, Teresa,Nigst, Tobias A.,De Rycke, Nicolas,Mayer, Peter,Wendt, Bernd,David, Olivier R. P.,Zipse, Hendrik
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supporting information
p. 6435 - 6442
(2013/07/05)
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- SUBSTITUTED HETEROCYCLIC AZA DERIVATIVES
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The invention relates to heterocyclic aza derivatives as vanilloid receptor ligands, to pharmaceutical compositions containing these compounds and also to these compounds for use in the treatment and/or prophylaxis of pain and further diseases and/or disorders.
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Page/Page column 143
(2013/03/26)
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- Substituted Heterocyclic Aza Compounds
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Heterocyclic aza compounds as vanilloid receptor ligands, pharmaceutical compositions containing these compounds and also methods of using these compounds for the treatment and/or inhibition of pain and further diseases and/or disorders.
- -
-
Paragraph 0815
(2013/03/26)
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- AZABENZOTHIAZOLE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
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Provided are compounds of Formula I, stereoisomers, tautomers, solvates, prodrugs and pharmaceutically acceptable salts thereof, wherein A, X, R1, R2, R4 and R5 are defined herein, a pharmaceutical composition that includes a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant or vehicle, methods of using the compound or composition in therapy, and methods of 5 manufacturing a compound of Formula I
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Page/Page column 76
(2012/04/04)
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- HETEROCYCLIC DERIVATIVES
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The present invention relates to heterocyclic derivatives, and more particularly, to novel heterocyclic derivatives useful for the preparation of medicaments for treating diseases related to uric acid.
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Page/Page column 16
(2011/02/25)
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- The catalytic potential of 4-guanidinylpyridines in acylation reactions
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A series of 3-alkyl-4-guanidinylpyridines with variable alkylation pattern have been synthesized and characterized with respect to their catalytic potential in acylation reactions of alcohols. The ability of the substitution pattern to stabilize acylpyridinium cations, which act as critical intermediates in the catalytic cycle of pyridine-catalyzed acylation reactions, has been assessed at the MP2(FC)/6-31+G(2d,p)//B98/6-31G(d) level of theory and inclusion of solvent effects in chloroform using the PCM continuum solvation model. The most active 4-guanidinylpyridines are among those having the most electron-rich pyridine ring. The influence of the type and concentration of the auxiliary base on the catalytic activity has also been studied. While the change from triethylamine to N,N-diisopropylethylamine as the auxiliary base does not lead to a systematic increase or decrease in the catalytic rates, the complete absence of auxiliary base leads to a 27-fold reduction in reaction rate. Georg Thieme Verlag Stuttgart.
- Held, Ingmar,Larionov, Evgeny,Bozler, Christian,Wagner, Felicia,Zipse, Hendrik
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experimental part
p. 2267 - 2277
(2009/12/31)
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- Synthesis and evaluation of novel 3,4,6-substituted 2-quinolones as FMS kinase inhibitors
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A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-qui
- Wall, Mark J.,Chen, Jinsheng,Meegalla, Sanath,Ballentine, Shelley K.,Wilson, Kenneth J.,DesJarlais, Renee L.,Schubert, Carsten,Chaikin, Margery A.,Crysler, Carl,Petrounia, Ioanna P.,Donatelli, Robert R.,Yurkow, Edward J.,Boczon, Lisa,Mazzulla, Marie,Player, Mark R.,Patch, Raymond J.,Manthey, Carl L.,Molloy, Christopher,Tomczuk, Bruce,Illig, Carl R.
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p. 2097 - 2102
(2008/12/21)
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- Synthesis of aza analogues of the anticancer agent batracylin
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Three series of pyrido-fused pyrimido[2,1-a]isoindol-7-ones were prepared from readily available (aminopyridinyl)(aryl)methanones by reduction followed by a Mitsunobu reaction with phthalimide and acid-catalysed cyclodehydration. This approach provides a wide variety of aza analogues of the antitumour agent batracylin.
- Martínez-Viturro, Carlos M.,Domínguez, Domingo
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p. 4707 - 4710
(2008/03/13)
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- AMINOPYRIMIDINE COMPOUNDS AND METHODS OF USE
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The invention relates to aminopyrimidine compounds useful for treating diseases mediated by polo-like kinase 1 (Plk1). The invention also relates to the therapeutic use of such aminopyrimidine compounds and compositions thereof in treating disease states associated with abnormal cell growth and unwanted cell proliferation.
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Page/Page column 48-49
(2010/11/08)
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- Non-imidazole histamine H3 ligands. Part III. New 4-n-propylpiperazines as non-imidazole histamine H3-antagonists
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In search for a new lead of non-imidazole histamine H3-receptor antagonists, a series of 1[(2-thiazolopyridine)-4-n-propyl]piperazines, the analogous 1-[(2-oxazolopyridine)-4-npropyl]piperazines, 1-[(2-benzothiazole)-4- n-propyl]piperazine and 1-[(2-benzooxazole)4-n-propyl]piperazine were prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). It appeared that by comparison of homologous pairs the thiazolo derivatives have slightly higher activity than their oxazolo analogues. The most potent compound of these series is the 1-(2-thiazolo[4,5-c]pyridine)-4-n-propylpiperazine (3c) with pA2 = 7.25 (its oxazole analogue (4g) showed pA2 = 6.9). The structure-activity relationships for compounds with various positions of the nitrogen in the benzene ring for the thiazoles compared with oxazoles are discussed.
- Walczyski, Krzysztof,Zuiderveld, Obbe P.,Timmerman, Henk
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- NAPHTHYRIDINE DERIVATIVES AND THEIR USE AS MODULATORS OF MUSCARINIC RECEPTORS
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A compound of formula (I) wherein: Ring A is aryl or heteroaryl; one of V, W, Y or Z is nitrogen and the other of V, W, Y and Z are -C(R5)-; modulate muscarinic receptors and are useful for treating muscarinic receptor mediated diseases.
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Page/Page column 20-21
(2008/06/13)
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- Inhibition studies with rationally designed inhibitors of the human low molecular weight protein tyrosine phosphatase
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The human low molecular weight protein tyrosine phosphatase (HCPTP) is ubiquitously expressed as two isoforms in a wide range of human cells and may be involved in regulating the metastatic nature of epithelial tumors. A homology model is presented for th
- Zabell, Adam P. R.,Corden, Steven,Helquist, Paul,Stauffacher, Cynthia V.,Wiest, Olaf
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p. 1867 - 1880
(2007/10/03)
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- CYCLOALKANEPYRROLOPYRIDINES AS DP RECEPTOR ANTAGONISTS
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Novel cycloalkanepyrrolopyridine derivatives are antagonists of prostaglandins, and as such are useful for the treatment of prostaglandin mediated diseases.
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- Synthesis of 2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-c]-[1,5]- thiazepin-3(2H)-one
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2-(4-Methoxyphenyl)pyrrolo[2,1-d]pyrido[2,3-c][1,5]thiazepin-3(2H)-one, a key intermediate in the synthesis of pyrrolopyridothiazepine derivatives, was synthesized from bis(4H-pyrrolo-3-pyridyl)disulfide and α-bromo-(4- methoxy-phenyl)acetic acid ethyl ester in order to develop a novel calcium channel antagonist.
- Ma, Eunsook
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p. 678 - 686
(2007/10/03)
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- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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-
-
- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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Page/Page column 24
(2010/01/31)
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- Azaindolylalkylamine derivatives as 5-hydroxytryptamine-6 ligands
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The present invention provides a compound of formula I and the use thereof for the therapeutic treatment of disorders relating to or affected by the 5-HT6 receptor.
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-
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- Modified aminoacids, pharmaceuticals containing these compounds and method for their production
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The present invention relates to modified amino acids of general formula wherein A, Z, X, n, m, R, R2, R3, R4and R11are defined as in claims 1 to 5, their tautomers, their diastereomers, their enantiomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for preparing them as well as their use for the production and purification of antibodies and as labelled compounds in RIA- and ELISA assays and as diagnostic or analytical aids in neurotransmitter research.
- -
-
Example A3a)
(2008/06/13)
-
- Regiospecific Electrophilic Substitution of Aminopyridines: Ortho Lithiation of 2-, 3-, and 4-(Pivaloylamino)pyridines
-
2- and 4-(pivaloylamino)pyridines have been shown to undergo metalation exclusively at C-3 and these smoothly react with a variety of electrophiles to produce 2,3- and 3,4-disubstituted pyridines, respectively.Removal of the pivaloyl protecting group results in overall electrophilic substitution of an aminopyridine.Utilization of this method is exemplified by efficient syntheses of 2- and 4-aminonicotinaldehydes.Minor modifications of the reaction conditions permitted exclusive ortho metalation of 2-(pivaloylamino)pyridines additionally functionalized by chloro, fluoro, or methyl groups.Although the major product from reaction of 3-(pivaloylamino)pyridine by this method was metalation at C-4, the reaction was complicated by substantial quantities of product derived from nucleophilic attack by n-butyllithium on the pyridine nucleus.
- Turner, James A.
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p. 3401 - 3408
(2007/10/02)
-
