14804-61-6Relevant academic research and scientific papers
Pharmacological characterization of [3H]VUF11211, a novel radiolabeled small-molecule inverse agonist 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
, p. 639 - 648 (2015)
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.
1,2,4-TRIAZOLINOE CB1 INHIBITORS
-
Page/Page column 46, (2021/09/11)
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).
SUBSTITUTED 4,6-DIHYDROSPIRO[[1,2,3]TRIAZOLO[4,5-B]PYRIDINE-7,3'-INDOLINE]-2',5(3H)-DIONE ANALOGUES
-
Paragraph 0069, (2021/02/19)
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.
Synthesis of α-methylstilbenes using an aqueous Wittig methodology and application toward the development of potent human aromatase inhibitors
Nielsen, Alexander J.,Raez-Villanueva, Sergio,Crankshaw, Denis J.,Holloway, Alison C.,McNulty, James
supporting information, p. 1395 - 1398 (2019/04/03)
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).
SUBSTITUTED ISOXAZOLOPYRIDAZINONES AND ISOTHIAZOLOPYRIDAZINONES AND METHODS OF USE
-
Paragraph 0652, (2017/04/04)
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.
Catalytic Carbocation Generation Enabled by the Mesolytic Cleavage of Alkoxyamine Radical Cations
Zhu, Qilei,Gentry, Emily C.,Knowles, Robert R.
, p. 9969 - 9973 (2016/08/16)
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.
Transition-Metal-Free Stereospecific Cross-Coupling with Alkenylboronic Acids as Nucleophiles
Li, Chengxi,Zhang, Yuanyuan,Sun, Qi,Gu, Tongnian,Peng, Henian,Tang, Wenjun
supporting information, p. 10774 - 10777 (2016/09/09)
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.
Scalable anti-Markovnikov hydrobromination of aliphatic and aromatic olefins
Galli, Marzia,Fletcher, Catherine J.,Del Pozo, Marc,Goldup, Stephen M.
supporting information, p. 5622 - 5626 (2016/07/06)
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.
SPIROPYRAZOLOPYRIDINE DERIVATIVES AND USES THEREOF FOR THE TREATMENT OF VIRAL INFECTIONS
-
, (2014/10/29)
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.
NOVEL TRPV3 MODULATORS
-
Paragraph 0374; 0395, (2013/06/27)
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.
