- Development of highly potent phosphodiesterase 10A (PDE10A) inhibitors: Synthesis and in vitro evaluation of 1,8-dipyridinyl- and 1-pyridinyl-substituted imidazo[1,5-a ]quinoxalines
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Herein we report the synthesis of fluorinated inhibitors of phosphodiesterase 10A (PDE10A) which can be used potentially as lead structure for the development of a 18F-labeled PDE10A imaging agent for positron emission tomography. The use of or
- Wagner, Sally,Scheunemann, Matthias,Dipper, Karolin,Egerland, Ute,Hoefgen, Norbert,Steinbach, J?rg,Brust, Peter
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Read Online
- Compounds and pharmaceutical compositions thereof for the treatment of inflammatory disorders
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The present invention discloses compounds according to Formula I: wherein Cy, R1, L1, R3, R4, R5, La, and Ra are as defined herein. Novel benzimidazoles according to Formula I, a
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Page/Page column 51; 52
(2017/01/09)
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- NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
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The present invention discloses compounds according to Formula I: wherein Cy, R1, L1, R3, R4, R5, La, and Ra are as defined herein. Novel benzimidazoles according to Formula I, a
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Paragraph 0421-0422
(2015/07/27)
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- BENZIMIDAZOLE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
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The present invention discloses compounds according to Formula (I) wherein Cy, R1, L1 R3, R4, R5, La, and Ra are as defined herein. Novel benzimidazoles according to Formula (I),
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Paragraph 00237
(2015/08/06)
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- Discovery of cyclic sulfone hydroxyethylamines as potent and selective β-site APP-cleaving enzyme 1 (BACE1) inhibitors: Structure-based design and in vivo reduction of amyloid β-peptides
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Structure-based design of a series of cyclic hydroxyethylamine BACE1 inhibitors allowed the rational incorporation of prime- and nonprime-side fragments to a central core template without any amide functionality. The core scaffold selection and the structure-activity relationship development were supported by molecular modeling studies and by X-ray analysis of BACE1 complexes with various ligands to expedite the optimization of the series. The direct extension from P1-aryl- and heteroaryl moieties into the S3 binding pocket allowed the enhancement of potency and selectivity over cathepsin D. Restraining the design and synthesis of compounds to a physicochemical property space consistent with central nervous system drugs led to inhibitors with improved blood-brain barrier permeability. Guided by structure-based optimization, we were able to obtain highly potent compounds such as 60p with enzymatic and cellular IC50 values of 2 and 50 nM, respectively, and with >200-fold selectivity over cathepsin D. Pharmacodynamic studies in APP51/16 transgenic mice at oral doses of 180 μmol/kg demonstrated significant reduction of brain Aβ levels.
- Rueeger, Heinrich,Lueoend, Rainer,Rogel, Olivier,Rondeau, Jean-Michel,M?bitz, Henrik,MacHauer, Rainer,Jacobson, Laura,Staufenbiel, Matthias,Desrayaud, Sandrine,Neumann, Ulf
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experimental part
p. 3364 - 3386
(2012/06/01)
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- TETRACYCLIC XANTHENE DERIVATIVES AND METHODS OF USE THEREOF FOR THE TREATMENT OF VIRAL DISEASES
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The present invention relates to novel Tetracyclic Xanthene Derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, Y1, Y2, Z, Ra, Rb, R1a, R1b and R2 are as defined herein. The present invention also relates to compositions comprising at least one Tetracyclic Xanthene Derivative, and methods of using the Tetracyclic Xanthene Derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 75
(2012/10/07)
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- TETRACYCLIC XANTHENE DERIVATIVES AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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The present invention discloses tetracyclic xanthene derivatives of Formula (I) and pharmaceutically acceptable salts thereof, wherein A, Y1, Y2, Z, Ra, Rb, R1a, R1b, and R2 are as defined herein. The present invention also discloses compositions comprising at least one tetracyclic xanthene derivative, and methods of using the tetracyclic xanthene derivatives for treating or preventing HCV infection in a patient.
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Page/Page column 94
(2012/10/07)
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- NOVEL BICYCLIC HETEROCYCLIC COMPOUND
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The present invention aims to provide a drug for the treatment or prophylaxis of pathology in general in which SNS is involved, specifically diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like. The present inventi
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Page/Page column 75
(2011/11/07)
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- BENZO[d]OXAZOLES AND BENZO[d]THIAZOLES AS KINASE INHIBITORS
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Novel benzo[d]oxazole and/or benzo[d]thiazole compounds, pharmaceutical compositions containing the benzo[d]oxazole and/or benzo[d]thiazole compounds, and methods of their pharmaceutical use are disclosed. In certain embodiments, the benzo[d]oxazole and/o
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Page/Page column 96
(2010/04/06)
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- Benzothiazoles as Rho-associated kinase (ROCK-II) inhibitors
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A series of benzothiazole derivatives as ROCK inhibitors have been discovered. Compounds with good biochemical and cellular potency, and sufficient kinase selectivity have been identified.
- Yin, Yan,Lin, Li,Ruiz, Claudia,Cameron, Michael D.,Pocas, Jennifer,Grant, Wayne,Schroeter, Thomas,Chen, Weimin,Duckett, Derek,Schuerer, Stephan,LoGrasso, Philip,Feng, Yangbo
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scheme or table
p. 6686 - 6690
(2010/06/14)
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- POLO-LIKE KINASE INHIBITORS
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Compounds of the following formula are provided for use with kinases: (I) wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates use
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Page/Page column 364
(2009/05/29)
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- Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: Intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships
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The discovery of new antibacterial agents with novel mechanisms of action is necessary to overcome the problem of bacterial resistance that affects all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV are well-characterized clinically validated targets of the fluoroquinolone antibiotics which exert their antibacterial activity through inhibition of the catalytic subunits. Inhibition of these targets through interaction with their ATP sites has been less clinically successful. The discovery and characterization of a new class of low molecular weight, synthetic inhibitors of gyrase and topoisomerase IV that bind to the ATP sites are presented. The benzimidazole ureas are dual targeting inhibitors of both enzymes and possess potent antibacterial activity against a wide spectrum of relevant pathogens responsible for hospital- and community-acquired infections. The discovery and optimization of this novel class of antibacterials by the use of structure-guided design, modeling, and structure-activity relationships are described. Data are presented for enzyme inhibition, antibacterial activity, and in vivo efficacy by oral and intravenous administration in two rodent infection models.
- Charifson, Paul S.,Grillot, Anne-Laure,Grossman, Trudy H.,Parsons, Jonathan D.,Badia, Michael,Bellon, Steve,Deininger, David D.,Drumm, Joseph E.,Gross, Christian H.,LeTiran, Arnaud,Liao, Yusheng,Mani, Nagraj,Nicolau, David P.,Perola, Emanuele,Ronkin, Steven,Shannon, Dean,Swenson, Lora L.,Tang, Qing,Tessier, Pamela R.,Tian, Ski-Kai,Trudeau, Martin,Wang, Tiansheng,Wei, Yunyi,Zhang, Hong,Stamos, Dean
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experimental part
p. 5243 - 5263
(2009/07/01)
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- COMPOUNDS WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE
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Compounds which have activity at M1 receptor and their uses in medicine Compounds of formula (I) and salts and solvates are provided: wherein R4 is fluoro, R5 is selected from hydrogen, halogen, cyano, C1-6alkyl
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Page/Page column 51
(2010/11/26)
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- Gyrase inhibitors and uses thereof
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The present invention relates to compounds that inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordin
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- Gyrase inhibitors and uses thereof
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The present invention relates to methods of treating, preventing, or lessening the severity of resistant bacterial infections in mammals, utilizing compounds of formula I or formula VII or pharmaceutically salts thereof. The present invention also relates
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- Gyrase inhibitors and uses thereof
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The present invention relates to compounds which inhibit bacterial gyrase and/or Topo IV and pharmaceutically acceptable compositions comprising said compounds. These compounds, and compositions thereof, are useful in treating bacterial infection. Accordi
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- RADICAL-ANIONS OF AROMATIC COMPOUNDS. XXI. THE RADICAL-ANIONS OF 4-SUBSTITUTED 2,6-DIFLUORO- AND 2,3,5,6-TETRAFLUORONITROBENZENES
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For the radical-anions of the series of 4-substituted nitrobenzenes it was established that it fluorine atoms are introduced at both ortho positions of the nitro group the sensitivity of the nature of the para substituent is increased for the spin-spin co
- Selivanova, G. A.,Starichenko, V. F.,Ryabinin, V. A.,Shteingarts, V. D.
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p. 1140 - 1147
(2007/10/02)
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