- Concentration-dependent supramolecular self-assembly of A1/A2-asymmetric-difunctionalized pillar[5]arene
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A series of A1/A2-bromoalkoxy-and-hydroxy-difunctionalized pillar[5]arenes were synthesized by the removal of the pillar[5]arene-bearing benzyl group using catalytic hydrogenation. The difunctionalized pillar[5]arene bearing 8-bromooctoxy and benzyloxy su
- Al-Azemi, Talal F.,Vinodh, Mickey
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p. 2995 - 3002
(2021/01/28)
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- PIPERAZINE DERIVATIVES FOR INFLUENZA VIRUS INHIBITION
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The present invention provides piperazine derivatives exhibiting high affinity to the stem region (viral membrane proximal part) of influenza hemagglutinin as determined through competition binding and high virus neutralization activity while having low c
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Page/Page column 23
(2018/08/26)
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- Synthesis of some novel pendant-armed cyclen derivatives
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A new easy-to-run route to some novel pendant-armed benzene-containing cyclen derivatives is proposed. In this route, the use of potassium carbonate instead of (N,N)-diisopropylethylamine as proton trapper caused a remarkable increase of yields.
- Wang, Aijian,Zhao, Wei,Sun, Xiaoqiang
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p. 551 - 554
(2016/01/20)
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- MONOACYLGLYCEROL LIPASE INHIBITORS FOR MODULATION OF CANNABINOID ACTIVITY
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Disclosed are compounds and compositions that inhibit the action of monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), methods of inhibiting MGL and FAAH, methods of modulating cannabinoid receptors, and methods of treating various disorders related to the modulation of cannabinoid receptors.
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Page/Page column 135
(2009/05/28)
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- LTA4H modulators and uses thereof
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Leukotriene A4 hydrolase (LTA4H) inhibitors, compositions containing them, and methods of use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and/or conditions associated with inflammation.
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Page/Page column 28
(2008/12/07)
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- Identification of a potent, selective, and orally active leukotriene A 4 hydrolase inhibitor with anti-inflammatory activity
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LTA4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA4H stereospecifically catalyzes the transformation of the unstable epoxide LTA4 to the diol LTB4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.
- Grice, Cheryl A.,Tays, Kevin L.,Savall, Brad M.,Wei, Jianmei,Butler, Christopher R.,Axe, Frank U.,Bembenek, Scott D.,Fourie, Anne M.,Dunford, Paul J.,Lundeen, Katherine,Coles, Fawn,Xue, Xiaohua,Riley, Jason P.,Williams, Kacy N.,Karlsson, Lars,Edwards, James P.
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experimental part
p. 4150 - 4169
(2009/07/19)
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- Phenyl and pyridyl LTA4H modulators
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Leukotriene A4 hydrolase (LTA4H) inhibitors, compositions containing them, and methods of use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and inflammatory conditions.
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Page/Page column 22
(2010/11/24)
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- BENZIMIDAZOLE, BENZTHIAZOLE AND BENZOXAZOLE DERIVATIVES AND THEIR USE AS LTA4H MODULATORS
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Leukotriene A4 hydrolase (LTA4H) inhibitors of formula I, compositions containing them, and their use for the inhibition of LTA4H enzyme activity and the treatment, prevention or inhibition of inflammation and/or conditions associated with inflammation, wherein X is selected from the group consisting of NR5, O, and S, with R5 being one of the H and CH3; Y is selected from the group consisting of CH2 and O; R4 is selected from the group consisting of H, OCH3, Cl, F, Br, I, OH, NH2, CN, CF3.
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Page/Page column 76
(2010/02/10)
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- 4-substituted piperidine analogs and their use as subtype selective NMDA receptor antagonists
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PCT No. PCT/US96/20872 Sec. 371 Date Sep. 16, 1998 Sec. 102(e) Date Sep. 16, 1998 PCT Filed Dec. 20, 1996 PCT Pub. No. WO97/23216 PCT Pub. Date Jul. 3, 1997Novel 4-substituted piperidine analogs, pharmaceutical compositions containing the same and the method of using 4-substituted piperidine analogs are selective active antagonists of N-methyl-D-aspartate (NMDA) receptor subtypes for treating conditions such as stroke, cerebral ischemia, central nervous system trauma, hypoglycemia, psychosis, anxiety, migraine headaches, glaucoma, CMV retinitis, aminoglycoside antibiotics-induced hearing loss, convulsions, chronic pain, opioid tolerance or withdrawal, urinary incontinence or neurodegenerative disorders, such as lathyrism, Alzheimer's Disease, Parkinsonism and Huntington's Disease are described.
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- 4-hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine: A novel, potent, and selective NR1/2B NMDA receptor antagonist
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A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC50 = 0.63 μM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for α1-adrenergic receptors and inhibition of neuronal K+ channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a ~25-fold increase in NR1A/2B potency (IC50 = 0.025 μM). p-Methyl substitution on the benzyl ring (10b) produced a ~3-fold increase in MES activity (ED50 = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for α1 receptors and reduction in inhibition of K+ channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4- hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.
- Zhou, Zhang-Lin,Cai, Sui Xiong,Whittemore, Edward R.,Konkoy, Christopher S.,Espitia, Stephen A.,Tran, Minhtam,Rock, David M.,Coughenour, Linda L.,Hawkinson, Jon E.,Boxer, Peter A.,Bigge, Christopher F.,Wise, Lawrence D.,Weber, Eckard,Woodward, Richard M.,Keana, John F. W.
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p. 2993 - 3000
(2007/10/03)
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- Squalene synthase inhibitors: Isosteric replacements of the farnesyl chain of benzyl farnesyl amine
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Squalene synthase catalyzes the committed step of cholesterol biosynthesis. We report here the synthesis and in vivo activity of a series of squalene synthase inhibitors that contain isosteric replacements for the farnesyl chain of the known inhibitor ben
- Brinkman, John A.,Damon, Robert E.,Fell, Jay B.,Perez, Lawerence B.,Scallen, Terence J.,Vedananda
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p. 2491 - 2494
(2007/10/03)
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- A reappraisal of the effect upon thymidine kinase of thymidine derivatives carrying large groups at the 5'-position
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Several thymidine derivatives with hydrophobic 5'-substituents, linked by chemically stable amide and ether links, were synthesized as potential thymidine kinase inhibitors. None of these was active nor were several derivatives of thymidine 5'-acetate, wh
- Barrie,Davies,Stock,Harrap
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p. 1044 - 1047
(2007/10/02)
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- SUBSTITUTED PHENOXY-AMINOPROPANOL DERIVATIVES
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Phenoxy-aminopropanol derivatives of the formula STR1 wherein R is lower alkyl, X is oxygen or sulfur, n is the integer zero or 1, Y is methylene, ethylene or propylene or, when n is zero, Y can also be a group of the formula EQU1 , wherein the double-bond is trans and the carbon atom marked with an asterisk is linked to Z, and Z is a 5-membered aromatic heterocyclic ring which contains one or more nitrogen atoms as the sole hetero atom (s), said heterocyclic ring is linked to Y via a nitrogen atom, and may be substituted by halogen, lower alkyl, lower alkoxy, aryl, cyano or carboxamido, or on adjacent carbon atoms by a group of the formula STR2 and pharmaceutically acceptable acid addition salts thereof are described. A process for the preparation of the compound of formula I and pharmaceutical preparations containing them are also described. The aforementioned compounds and salts possess β-adrenergic blocking activity and antihypertensive activity.
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