- First no-carrier-added radioselenation of an adenosine-A1 receptor ligand
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The precursor synthesis and the no-carrier-added (n.c.a.) radiosynthesis of the adenosine-A1 receptor ligand 5′-(methyl[ 75Se]seleno)-N6-cyclopentyladenosine ([75Se]1) are described in this report. A method was developed starting from elemental n.c.a. selenium-75, followed by a three-step polymer-supported radioselenation and deprotection which gave the radioligand with a radiochemical yield of 30%, a radiochemical purity of > 99% and a specific radioactivity of > 300 GBq/mmol (8 Ci/mmol). Preparation time was 40 min. The nonradioactive compound 5′-(methylseleno)-N6-cyclopentyladenosine (1) was pharmacologically evaluated in vitro and showed high affinity and selectivity for the adenosine-A1 receptor. These preliminary results suggest that this compound could be a useful radioligand for the noninvasive imaging of the brain adenosine-A1 receptors using positron emission tomography (PET) when labelled with the positron emitter selenium-73 (half-life: 7.1 h). Copyright
- Blum, Till,Ermert, Johannes,Wutz, Walter,Bier, Dirk,Coenen, Heinz H.
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Read Online
- Synthesis and ability of new ligands for G protein-coupled receptors 17 (GPR17)
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Background: GPR17 is believed to be a novel target for the development of new therapeutic approaches to human stroke and multiple sclerosis. Hence, the selection of GPR17 ligands may be a potent way to reduce the progression of ischemic damage. Material/Methods: New potential ligands for GPR17, mono-, di-, and triphosphate adenosine nucleotides substituted at N6-position with a methyl and a cyclopentyl group were synthesized. The ability of new ligands to bind GPR17 was evaluated using frontal affinity chromatography-mass spectrometry (FAC-MS) method. Cangrelor, MRS2179, and uridine diphosphate were selected as the reference compounds. Results: The new triphosphate derivatives 9 and 10 were considered as the new GPR17 ligands. The compound 10 was eluted with breakthrough time (bt) between cangrelor and MRS 2179 (compound 10, bt=12.25; cangrelor, bt=24.55, and MRS 2179, bt=7.10), while the breakthrough volume of compound 9 was similar to that of MRS 2179 (compound 9, bt=7.53 and MRS 2179, bt=7.10). Conclusions: N6-cyclopentyATP 10 is medium-high affinity ligand of GPR17, while the corresponding N6-methyl derivative 9 is a medium affinity ligand similar to MRS 2179. Hence, the new N6-cyclopentylATP 10 might be a good candidate for the pharmacological characterization of GPR17.
- Zhuo, Tongyou,Zhou, Shengxue,Zhang, Wei,Lambertucci, Catia,Volpini, Rosaria
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p. 953 - 959
(2017/03/20)
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- METHODS OF PREVENTING, REDUCING OR TREATING MACULAR DEGENERATION
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The present invention is directed to selective adenosine A1 agonist compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat, reduce or prevent age-related macular degeneration.
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Page/Page column 44
(2016/06/28)
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- METHOD OF PROVIDING OCULAR NEUROPROTECTION
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Provided herein are compounds of Formula I, compositions comprising an effective amount of a compound of Formula I, and methods for preventing, reducing or treating retinal ganglion cell damage comprising administering an effective amount of a purine deri
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Paragraph 0173
(2014/09/30)
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- OPHTHALMIC FORMULATIONS
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The present invention relates to an ophthalmic formulation which comprises a fine particle of Compound A in an aqueous suspension and a manufacturing process thereof. More specifically, the present invention relates to a topically applied ophthalmic aqueous suspension which is obtainable by suspending fine particles of Compound A in an aqueous vehicle containing a surfactant and boric acid. The invention also provides processes for making the ophthalmic formulations and to methods of use thereof.
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Paragraph 0100
(2014/09/29)
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- ANHYDROUS POLYMORPHS OF [(2R,3S,4R,5R)-5-(6-(CYCLOPENTYLAMINO)-9H-PURIN-9-YL)-3,4-DIHYDROXYTETRAHYDROFURAN-2-YL)} METHYL NITRATE AND PROCESSES OF PREPARATION THEREOF
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The present invention provides novel anhydrous polymorph forms of 2R,3S,4R,5R)-5-(6-(cyclopentylamino)-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl nitrate (Compound A). The present invention also provides processes for preparation of the anhydrous polymorphic forms of compound A.
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Paragraph 0077
(2013/08/14)
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- COMBINATION, KIT AND METHOD OF REDUCING INTRAOCULAR PRESSURE
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The present invention is directed to a combination or a kit comprising a prostaglandin analog and an adenosine receptor A1 agonist and to a method of reducing intraocular pressure (IOP) in a subject using such combination or kit. The invention is particularly directed to a combination of latanoprost marketed under the brand Xalatan? and Compound A.
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- Regioselective alkylation of the exocyclic nitrogen of adenine and adenosine by the Mitsunobu reaction
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A novel synthetic route to N6-substitution of adenine is presented, employing the Mitsunobu reaction as the key step. A range of primary and secondary alcohols all coupled in very good to excellent yields within 30 min at 45 °C, offering a milder alternative to the traditional nucleophilic aromatic substitution of 6-chloropurine. The utility of this protocol is further demonstrated by its application to the syntheses of N6,N9-di-substituted adenines, including the potent and selective A1 adenosine receptor agonist N6-cyclopentyladenosine.
- Fletcher, Steven
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scheme or table
p. 2948 - 2950
(2010/06/21)
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- N6-Alkyladenosines: Synthesis and evaluation of in vitro anticancer activity
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A series of adenosine analogues differently substituted in N 6-position were synthesized to continue our studies on the relationships between structure and biological activity of iPA. The structures of the compounds were confirmed by standard studies of 1H NMR, MS and elemental analysis. These molecules were then evaluated for their anti-proliferative activity on bladder cancer cells. We found that some of these compounds possess anti-proliferative activity but have no effect on cell invasion and metalloprotease activity.
- Ottria, Roberta,Casati, Silvana,Baldoli, Erika,Maier, Jeanette A.M.,Ciuffreda, Pierangela
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experimental part
p. 8396 - 8402
(2011/02/22)
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- METHOD OF REDUCING INTRAOCULAR PRESSURE IN HUMANS
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Provided herein are compounds of Formula I, compositions comprising an effective amount of a compound of Formula I, and methods for reducing intraocular pressure comprising administering an effective amount of compounds of Formula I to a subject in need t
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Page/Page column 34
(2010/11/17)
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- Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: Structure-activity relationships of the nucleobase domain of 5′-O-[N-(salicyl)sulfamoyl]adenosine
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5′-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC99 under iron-deficient conditions of 0.049 μM while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence.
- Neres, Jo?o,Labello, Nicholas P.,Somu, Ravindranadh V.,Boshoff, Helena I.,Wilson, Daniel J.,Vannada, Jagadeshwar,Chen, Liqiang,Barry III, Clifton E.,Bennett, Eric M.,Aldrich, Courtney C.
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experimental part
p. 5349 - 5370
(2009/07/01)
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- Purine compounds and methods of use thereof
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The invention relates to Purine Compounds; compositions comprising an effective amount of a Purine Compound; and methods for reducing a subject's rate of metabolism or protecting a subject's heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular disease, a neurological disorder, an ischemic condition, a reperfusion injury, obesity, a wasting disease, diabetes, a cellular proliferative disorder, a skin disorder, a radiation-induced injury, a wound or an inflammatory disease comprising administering an effective amount of a Purine Compound to a subject in need thereof.
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Page/Page column 130
(2008/06/13)
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- PURINE DERIVATIVES AS ADENOSINE A1 RECEPTOR AGONISTS AND METHODS OF USE THEREOF
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The invention relates to Purine Derivatives, compositions comprising an effective amount of a Purine Derivative; and methods for reducing an animal’s rate of metabolism, protecting an animal’s heart against myocardial damage during cardioplegia; or for treating or preventing a cardiovascular disease, a neurological disorder, an ischemic condition, a reperfusion injury, obesity, or wasting disease, or diabetes, comprising administering an effective amount of a Purine Derivative to an animal in need thereof.
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Page/Page column 131
(2008/06/13)
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- Partial and full agonists of A1 adenosine receptors
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Disclosed are novel compounds that are partial and full A1 adenosine receptor agonists, useful for treating various disease states, in particular tachycardia and atrial flutter, angina, myocardial infarction and hyperlipidemia.
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- Design of allele-specific protein methyltransferase inhibitors
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Protein arginine methyltransferases, which catalyze the transfer of methyl groups from S-adenosylmethionine (SAM) to arginine side chains in target proteins, regulate transcription, RNA processing, and receptor-mediated signaling. To specifically address the functional role of the individual members of this family, we took a "bump-and-hole" approach and designed a series of N6-substituted S-adenosylhomocysteine (SAH) analogues that are targeted toward a yeast protein methyltransferase RMT1. A point mutation was identified (E117G) in Rmt1 that renders the enzyme susceptible to selective inhibition by the SAH analogues. A mass spectrometry based enzymatic assay revealed that two compounds, N6-benzyl- and N6-naphthylmethyl-SAH, can inhibit the mutant enzyme over the wild-type with the selectivity greater than 20. When the E117G mutation was introduced into the Saccharomyces cerevisiae chromosome, the methylation of Np13p, a known in vivo Rmt1 substrate, could be moderately reduced by N6-naphthylmethyl-SAH in the resulting allele. In addition, an N6-benzyl-SAM analogue was found to serve as an orthogonal SAM cofactor. This analogue is preferentially utilized by the mutant methyltransferase relative to the wild-type enzyme with a selectivity greater than 67. This specific enzyme/inhibitor and enzyme/substrate design should be applicable to other members of this protein family and facilitate the characterization of protein methyltransferase function in vivo when combined with RNA expression analysis.
- Lin,Jiang,Schultz,Gray
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p. 11608 - 11613
(2007/10/03)
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- N-cycloalkyl derivatives of adenosine and 1-deazaadenosine as agonists and partial agonists of the A1 adenosine receptor
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A number of cycloalkyl substituents (from C-3 to C-8) have been introduced on the 6-amino group of adenosine, 1-deazaadenosine, and 2'- deoxyadenosine, bearing or not a chlorine atom at the 2-position, to evaluate the influence on the A1 and A(
- Vittori, Sauro,Lorenzen, Anna,Stannek, Christina,Costanzi, Stefano,Volpini, Rosaria,Ijzerman, Adriaan P.,Von Frijtag Drabbe Kunzel, Jakobien K.,Cristalli, Gloria
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p. 250 - 260
(2007/10/03)
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- Adenosine analogues as inhibitors of Trypanosoma brucei phosphoglycerate kinase: Elucidation of a novel binding mode for a 2-Amino-N6-substituted adenosine
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As part of a project aimed at structure-based design of adenosine analogues as drugs against African trypanosomiasis, N6-, 2-amino-N6-, and N2-substituted adenosine analogues were synthesized and tested to establish structure - activity relationships for inhibiting Trypanosoma brucei glycosomal phosphoglycerate kinase (PGK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and glycerol-3-phosphate dehydrogenase (GPDH). Evaluation of X-ray structures of parasite PGK, GAPDH, and GPDH complexed with their adenosyl-bearing substrates led us to generate a series of adenosine analogues which would target all three enzymes simultaneously. There was a modest preference by PGK for N6-substituted analogues bearing the 2-amino group. The best compound in this series, 2-amino-N6-[2-(p-hydroxyphenyl)ethyl]adenosine (46b), displayed a 23-fold improvement over adenosine with an IC50 of 130 μM. 2-[[2-(p-Hydroxyphenyl)ethyl]amino]adenosine (46c) was a weak inhibitor of T. brucei PGK with an IC50 of 500 μM. To explore the potential of an additive effect that having the N6 and N2 substitutions in one molecule might provide, the best ligands from the two series were incorporated into N6,N2-disubstituted adenosine analogues to yield N6-(2-phenylethyl)-2-[(2-phenylethyl)amino]adenosine (69) as a 30 μM inhibitor of T. brucei PGK which is 100-fold more potent than the adenosine template. In contrast, these series gave no compounds that inhibited parasitic GAPDH or GPDH more than 10-20% when tested at 1.0 mM. A 3.0 A? X-ray structure of a T. brucei PGK/46b complex revealed a binding mode in which the nucleoside analogue was flipped and the ribosyl moiety adopted a syn conformation as compared with the previously determined binding mode of ADP. Molecular docking experiments using QXP and SAS program suites reproduced this 'flipped and rotated' binding mode.
- Bressi,Choe,HoughHough,Buckner,Van Voorhis,Verlinde,Hol,Gelb
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p. 4135 - 4150
(2007/10/03)
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- Selective tight binding inhibitors of trypanosomal glyceraldehyde-3- phosphate dehydrogenase via structure-based drug design
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Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from the sleeping sickness parasite Trypanosoma brucei is a rational target for anti- trypanosomatid drug design because glycolysis provides virtually all of the energy for the bloodstream form of this parasite. Glycolysis is also an important source of energy for other pathogenic parasites including Trypanosoma cruzi and Leishmania mexicana. The current study is a continuation of our efforts to use the X-ray structures of T. brucei and L. mexicana GAPDHs containing bound NAD+ to design adenosine analogues that bind tightly to the enzyme pocket that accommodates the adenosyl moiety of NAD+. The goal was to improve the affinity, selectivity, and solubility of previously reported 2'-deoxy-2'-(3-methoxybenzamido)adenosine (1). It was found that introduction of hydroxyl functions on the benzamido ring increases solubility without significantly affecting enzyme inhibition. Modifications at the previously unexploited N6-position of the purine not only lead to a substantial increase in inhibitor potency but are also compatible with the 2'-benzamido moiety of the sugar. For N6-substituted adenosines, two successive rounds of modeling and screening provided a 330-fold gain in affinity versus that of adenosine. The combination of N6- and 2'- substitutions produced significantly improved inhibitors. N6-Benzyl (9a) and N6-2-methylbenzyl (9b) derivatives of 1 display IC50 values against L. mexicana GAPDH of 16 and 4 μM, respectively (3100- and 12500-fold more potent than adenosine). The adenosine analogues did not inhibit human GAPDH. These studies underscore the usefulness of structure-based drug design for generating potent and species-selective enzyme inhibitors of medicinal importance starting from a weakly binding lead compound.
- Aronov, Alex M.,Verlinde, Christophe L. M. J.,Hol, Wim G. J.,Gelb, Michael H.
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p. 4790 - 4799
(2007/10/03)
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- N6,C8-distributed adenosine derivatives as partial agonists for adenosine A1 receptors.
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The synthesis and biological evaluation of N6, C8-disubstituted derivatives of adenosine as potential partial agonists for adenosine receptors is described. Via three routes, two series of compounds were prepared, viz., N6-cyclopentyladenosine derivatives 3a-e and C8-(cyclopentylamino)adenosine analogs 3e and 9a-d, respectively. The X-ray structure determination of one of these compounds, N6-ethyl-8(cyclopentylamino)adenosine (9b), was carried out (orthorhombic, space group P2(1)2(1)2(1) (No. 19) with a = 11.039(3), b = 8.708(2), and c = 24.815(12) angstrom, Z=4,R1=0.0974,R2(W) = 0.2455). Due to intramolecular hydrogen bonding, the ribose moiety of this compound is in an anti conformation. The compounds were tested in vitro in radioligand binding studies, yielding their affinities for A1 and A2a adenosine receptors. All compounds appeared A1 selective, with affinities in the high nanomolar, low micromolar range. On A1 receptors the so-called GTP shift was also determined, i.e., the ratio between the affinities measured in the presence and absence of 1 mM GTP. All GTP shifts (values between 1.1 and 3.8) were lower than the GTP shift for CPA (6.0). This GTP shift appeared indicative for partial agonism in vivo, since the N6-cyclopentyladenosine derivatives showed lower intrinsic activities than the prototypic full agonist N6-cyclopentyladenosine on the decrease in heart rate in conscious, normotensive rats.
- Roelen,Veldman,Spek,von Frijtag Drabbe Kuenzel,Mathot,IJzerman
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p. 1463 - 1471
(2007/10/03)
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