- Pharmacological characterization of [3H]VUF11211, a novel radiolabeled small-molecule inverse agonist for the chemokine receptor CXCR3
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Chemokine receptor CXCR3 has attracted much attention, as it is thought to be associated with a wide range of immunerelated diseases. As such, several small molecules with different chemical structures targeting CXCR3 have been discovered. Despite limited clinical success so far, these compounds serve as interesting tools for investigating receptor activation and antagonism. Accumulating evidence suggests that many of these compounds are allosteric modulators for CXCR3. One feature of allosteric ligands is that the magnitude of the mediated allosteric effect is dependent on the orthosteric probe that is used. Consequently, there is a risk for incorrect assessment of affinity for allosteric modulators with orthosteric radioligands, which has so far been the most applied approach for chemokine receptors. Therefore, we aimed to use a small-molecule allosteric ligand from the piperazinyl-piperidine class, also known as VUF11211 [(S)-5- chloro-6-(4-(1-(4-chlorobenzyl)piperidin-4-yl)-3-ethylpiperazin- 1-yl)-N-ethylnicotinamide]. VUF11211 acts as an inverse agonist at a constitutively active mutant of CXCR3. Radiolabeling of VUF11211 gave [3H]VUF11211, which in radioligand binding studies shows high affinity for CXCR3 (Kd 5 0.65 nM) and reasonably fast association (kon5 0.03 minute-1nM21) and dissociation kinetics (koff 5 0.02 minute21). The application of the [3H]VUF11211 to assess CXCR3 pharmacology was validated with diverse classes of CXCR3 compounds, including both antagonists and agonists, as well as VUF11211 analogs. Interestingly, VUF11211 seems to bind to a different population of CXCR3 conformations compared with the CXCR3 agonists CXC chemokine ligand 11 (CXCL11), VUF11418 [1-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)- N-((29-iodobiphenyl-4-yl)methyl)-N,N-dimethylmethanaminium Iodide], and VUF10661 [N-(6- Amino-1-(2,2-diphenylethylamino)- 1-oxohexan-2-yl)-2-(4-oxo-4-phenylbutanoyl)-1,2,3,4- Tetrahydroisoquinoline- 3-carboxamide]. These findings, taken together, indicate that this allosteric inverse agonist radioligand for CXCR3 may facilitate the discovery, characterization, and optimization of allosteric modulators for the chemokine receptor CXCR3.
- Scholten, Danny J.,Wijtmans, Maikel,Van Senten, Jeffrey R.,Custers, Hans,Stunnenberg, Ailas,De Esch, Iwan J. P.,Smit, Martine J.,Leurs, Rob
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Read Online
- 1,2,4-TRIAZOLINOE CB1 INHIBITORS
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Disclosed are compounds according to Formula (I), and related pharmaceutical compositions. Also disclosed are therapeutic methods, e.g., of treating diseases such as diabetic kidney disease, diabetic nephropathy, obesity-related kidney disease, focal segmental glomerular sclerosis, IgA nephropathy, nephrotic syndrome, kidney fibrosis, Prader Willi syndrome, metabolic syndrome, gastrointestinal diseases, non-alcoholic liver disease, alcoholic liver disease, or non-alcoholic fatty liver disease, using the compounds of Formula (I).
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Page/Page column 46
(2021/09/11)
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- SUBSTITUTED 4,6-DIHYDROSPIRO[[1,2,3]TRIAZOLO[4,5-B]PYRIDINE-7,3'-INDOLINE]-2',5(3H)-DIONE ANALOGUES
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A series of substituted 4,6-dihydrospiro[[1,2,3]triazolo[4,5-b]pyridine-7,3′-indoline]-2′,5(3H)-dione analogues, the use thereof and the preparation thereof.
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Paragraph 0069
(2021/02/19)
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- Synthesis of α-methylstilbenes using an aqueous Wittig methodology and application toward the development of potent human aromatase inhibitors
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The development of aqueous Wittig methodology for the synthesis of α-methylstilbenes using tripropylphosphine-derived phosphonium salts is described. The Wittig olefination reaction was high yielding and allowed isolation of stilbenes by simple filtration and washing with water. The novel phosphonium salts employed were accessed via a highly efficient, regioselective addition of hydrogen bromide to styrenes. Application of the α-methylstilbenes toward the synthesis of a collection of stilbenoid-triazoles is reported and their inhibition of CYP450 19A1 (aromatase) investigated. The overall structure-activity profile provided additional evidence on the aryl halide-ketone bioisostere hypothesis and identified 6c as a potent inhibitor of aromatase in vitro (Ki = 8 nM).
- Nielsen, Alexander J.,Raez-Villanueva, Sergio,Crankshaw, Denis J.,Holloway, Alison C.,McNulty, James
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supporting information
p. 1395 - 1398
(2019/04/03)
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- SUBSTITUTED ISOXAZOLOPYRIDAZINONES AND ISOTHIAZOLOPYRIDAZINONES AND METHODS OF USE
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Compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by positive allosteric modulation of the γ-aminobutyric acid B (GABA-B) receptor. Methods for making the compounds are described. Also described are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.
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Paragraph 0652
(2017/04/04)
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- Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations
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A new catalytic method is described to access carbocation intermediates via the mesolytic cleavage of alkoxyamine radical cations. In this process, electron transfer between an excited state oxidant and a TEMPO-derived alkoxyamine substrate gives rise to a radical cation with a remarkably weak C?O bond. Spontaneous scission results in the formation of the stable nitroxyl radical TEMPO.as well as a reactive carbocation intermediate that can be intercepted by a wide range of nucleophiles. Notably, this process occurs under neutral conditions and at comparatively mild potentials, enabling catalytic cation generation in the presence of both acid sensitive and easily oxidized nucleophilic partners.
- Zhu, Qilei,Gentry, Emily C.,Knowles, Robert R.
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p. 9969 - 9973
(2016/08/16)
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- Transition-Metal-Free Stereospecific Cross-Coupling with Alkenylboronic Acids as Nucleophiles
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We herein report a transition-metal-free cross-coupling between secondary alkyl halides/mesylates and aryl/alkenylboronic acid, providing expedited access to a series of nonchiral/chiral coupling products in moderate to good yields. Stereospecific SN2-type coupling is developed for the first time with alkenylboronic acids as pure nucleophiles, offering an attractive alternative to the stereospecific transition-metal-catalyzed C(sp2)-C(sp3) cross-coupling.
- Li, Chengxi,Zhang, Yuanyuan,Sun, Qi,Gu, Tongnian,Peng, Henian,Tang, Wenjun
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supporting information
p. 10774 - 10777
(2016/09/09)
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- Scalable anti-Markovnikov hydrobromination of aliphatic and aromatic olefins
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To improve access to a key synthetic intermediate we targeted a direct hydrobromination-Negishi route. Unsurprisingly, the anti-Markovnikov addition of HBr to estragole in the presence of AIBN proved successful. However, even in the absence of an added initiator, anti-Markovnikov addition was observed. Re-examination of early reports revealed that selective Markovnikov addition, often simply termed "normal" addition, is not always observed with HBr unless air is excluded, leading to the rediscovery of a reproducible and scalable initiator-free protocol.
- Galli, Marzia,Fletcher, Catherine J.,Del Pozo, Marc,Goldup, Stephen M.
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supporting information
p. 5622 - 5626
(2016/07/06)
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- SPIROPYRAZOLOPYRIDINE DERIVATIVES AND USES THEREOF FOR THE TREATMENT OF VIRAL INFECTIONS
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A compound of Formula (I) is provided that has been shown to be useful for treating a disease caused by a viral infection: (I) wherein R1, R2, R3, R4, R5, R6, R7, R8, X1, X2, X3 and X4, are as defined herein.
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- NOVEL TRPV3 MODULATORS
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Disclosed herein are modulators of TRPV3 of formula (I) wherein G1, X1, X2, X3, X4, X5, G2, Z1, Ra, Rb, u, and p are as defined in the specification. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also presented.
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Paragraph 0374; 0395
(2013/06/27)
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- MODULATORS OF METHYL MODIFYING ENZYMES, COMPOSITIONS AND USES THEREOF
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Agents for modulating methyl modifying enzymes, compositions and uses thereof are provided herein.
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Paragraph 00330; 00331
(2013/08/28)
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- In situ generation of diimide from hydrazine and oxygen: Continuous-flow transfer hydrogenation of olefins
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No catalyst required! A highly efficient, catalyst-free process to generate diimide in situ from hydrazine monohydrate and molecular oxygen for the selective reduction of alkenes has been developed. The use of a gas-liquid segmented flow system allowed safe operating conditions and dramatically enhanced this atom-economical reaction, resulting in short processing times. Copyright
- Pieber, Bartholomaeus,Martinez, Sabrina Teixeira,Cantillo, David,Kappe, C. Oliver
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supporting information
p. 10241 - 10244
(2013/10/21)
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- Catalytic enantioselective cross-couplings of secondary alkyl electrophiles with secondary alkylmetal nucleophiles: Negishi reactions of racemic benzylic bromides with achiral alkylzinc reagents
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We have developed a nickel-catalyzed method for the asymmetric cross-coupling of secondary electrophiles with secondary nucleophiles, specifically, stereoconvergent Negishi reactions of racemic benzylic bromides with achiral cycloalkylzinc reagents. In contrast to most previous studies of enantioselective Negishi cross-couplings, tridentate pybox ligands are ineffective in this process; however, a new, readily available bidentate isoquinoline-oxazoline ligand furnishes excellent ee's and good yields. The use of acyclic alkylzinc reagents as coupling partners led to the discovery of a highly unusual isomerization that generates a significant quantity of a branched cross-coupling product from an unbranched nucleophile.
- Binder, Joerg T.,Cordier, Christopher J.,Fu, Gregory C.
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supporting information
p. 17003 - 17006,4
(2012/12/11)
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- Catalytic enantioselective cross-couplings of secondary alkyl electrophiles with secondary alkylmetal nucleophiles: Negishi reactions of racemic benzylic bromides with achiral alkylzinc reagents
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We have developed a nickel-catalyzed method for the asymmetric cross-coupling of secondary electrophiles with secondary nucleophiles, specifically, stereoconvergent Negishi reactions of racemic benzylic bromides with achiral cycloalkylzinc reagents. In contrast to most previous studies of enantioselective Negishi cross-couplings, tridentate pybox ligands are ineffective in this process; however, a new, readily available bidentate isoquinoline-oxazoline ligand furnishes excellent ee's and good yields. The use of acyclic alkylzinc reagents as coupling partners led to the discovery of a highly unusual isomerization that generates a significant quantity of a branched cross-coupling product from an unbranched nucleophile.
- Binder, Joerg T.,Cordier, Christopher J.,Fu, Gregory C.
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supporting information
p. 17003 - 17006
(2013/01/15)
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- ORGANIC TELLURIUM COMPOUND, PROCESS FOR PRODUCING THE SAME, LIVING RADICAL POLYMERIZATION INITIATOR, PROCESS FOR PRODUCING POLYMER WITH THE SAME, AND POLYMER
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An organotellurium compound of the formula (1) is useful as a living radical polymerization initiator and makes possible precision control of molecular weights and molecular weight distributions under mild conditions wherein R1 is C1-C8 alkyl, R2 and R3 are each a hydrogen atom or C1-C8 alkyl, and R4 is aryl, substituted aryl, aromatic heterocyclic group, hydroxycarbonyl or cyano.
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Page/Page column 8
(2010/02/11)
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- An efficient and fast method for the preparation of benzylic bromides
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A mixture of triphenylphosphine and N-bromosuccinimide system is found to promote efficient conversion of benzylic alcohols into benzylic bromides under microwave irradiation conditions.
- Lee, Jong Chan,Hwang, Eui Yong
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p. 2959 - 2963
(2007/10/03)
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- Substrate activation: Indirect β-bromination of alcohols
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The reversible oxidation of an alcohol into a ketone provides access to enol/enolate chemistry. Preliminary results have applied this principle to the β-bromination of alcohols.
- Cami-Kobeci, Gerta,Williams, Jonathan M.J.
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p. 124 - 126
(2007/10/03)
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- Glucose transport-enhancing and hypoglycemic activity of 2-methyl-2- phenoxy-3-phenylpropanoic acids
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A series of 2-phenoxy-3-phenylpropanoic acids has been prepared which contains many potent hypoglycemic agents as demonstrated by assessing glucose lowering in ob/ob mice. Some compounds (32, 33, 59) normalize plasma glucose in this diabetic model at doses of approximately 1 mg/kg. The mechanism of action of these drugs may involve enhanced glucose transport, especially in fat cells, but the compounds do not stimulate GLUT4 translocation and do not increase the levels of GLUT1 or GLUT4 in vivo. Thus, these compounds may enhance the intrinsic activity of the glucose transporter GLUT1 or GLUT4. Some compounds also modestly decrease hepatocyte gluconeogenesis in vitro, but this is not likely to be a major contributor to the hypoglycemic effect observed in vivo. Likewise, a modest decrease in food consumption observed with some of these compounds was shown by a pair-feeding experiment not to be the primary cause of the hypoglycemia observed.
- Sarges,Hank,Blake,Bordner,Bussolotti,Hargrove,Treadway,Gibbs
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p. 4783 - 4803
(2007/10/03)
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- Trimethylamine-Borane Bromide as Alternative Reagent for Reductive Bromation of Aromatic Carbonyl Compounds
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The reaction of bromine with aromatic carbonyl compounds and trimethylamine-borane in chloroform leads to benzyl bromides.
- Corre, Maurice Le,Gheerbrant, Emmanual,Deit, Herve Le
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p. 313 - 314
(2007/10/02)
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- Synthesis of 3-Phenoxybenzyl 3-Alkyl-3-phenyl-/p-substituted phenyl and 3-Phenoxybenzyl 2-Alkyl-3-phenyl-/p-substituted phenylpropionates
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Some 3-phenoxybenzyl 3-alkyl-3-phenyl-/p-substituted phenylpropionates (VII, XI, XV, XIX, XXIII, XXVII) which resemble structurally the 1,2-secopyrethroids, have been prepared employing simple reactions like alkylation, decarbethoxylation and transesterification.The synthesis of 3-phenoxybenzyl 2-alkyl-3-phenyl-/p-substituted phenyl-propionates (XXXI, XXXII, XXXIII, and XXXVI) bearing close structural resemblance to 2,3-secopyrethroids has also been described.
- Kelkar, S. V.,Joshi, G. S.,Kulkarni, G. H.,Mitra, R. B.
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- Studies in Nucleophilic Substitutions: Part I - Reactions between Phenylmethylcarbinols and Hydrobromic Acid and Structure-Reactivity Analysis
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The kinetics of the reactions of phenylmethylcarbinol (PMC) and substituted PMCs with hydrobromic acid have been studied in 100percent acetic acid.The reaction rate follows total second order, first order each in and .The effect of substituents in the phenyl ring on the rate of substitution has been studied.The analysis of the rate data in terms of the Hammett equation gives a concave-down type of curve, though the Exner plot is linear.A stepwise mechanism involving the equilibrium formation of the conjugate acid of the alcohol followed by an attack by Br(-) accounts for the observed structure-reactivity pattern.
- Ramakrishnan, S.,Venkatasubramanian, N.
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