III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl–piperazinyl–piperidine scaffold

Kim, Seong Heon; Anilkumar, G.; Zawacki, Lisa Guise; Zeng, Qingbei; Yang, Deyi; Shao, Yinming; Dong, Guizhen; Xu, Xiaolian; Yu, Wei; Jiang, Yunlei; Jenh, Chung‐Her; Hall, Jeremy L.; Carroll, Carolyn DiIanni; Hobbs, Doug W.; Baldwin, John J.; McGuinness, Brian; Rosenblum, Stuart B.; Kozlowski, Joseph A.; Shankar, B. B.; Shih, Neng‐Yang

doi:10.1016/j.bmcl.2011.09.120

Cited by 17 publications

(13 citation statements)

References 13 publications

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“…65,66,70-73 Based on reported synthetic procedures for amilorides and other analogous compounds, 74-77 we designed and tested several synthetic routes to achieve diversity at the C(5) and C(6) positions (Schemes 1 – 5) of the core pyrazine ring. C(5) derivatives were achieved through a concise two-step pathway (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

et al. 2017

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Diversification of RNA-targeted scaffolds offers great promise in the search for selective ligands of therapeutically relevant RNA such as HIV-1 TAR. We herein report the establishment of amiloride as a novel RNA-binding scaffold along with synthetic routes for combinatorial C(5)- and C(6)-diversification. Iterative modifications at the C(5)- and C(6)- positions yielded derivative 24, which demonstrated a 100-fold increase in activity over the parent dimethylamiloride in peptide displacement assays. NMR chemical shift mapping was performed using the 2D SOFAST- [1H-13C] HMQC NMR method, which allowed for facile and rapid evaluation of binding modes for all library members. Cheminformatic analysis revealed distinct differences between selective and non-selective ligands. In this study, we evolved dimethylamiloride from a weak TAR ligand to one of the tightest binding selective TAR ligands reported to date through a novel combination of synthetic methods and analytical techniques. We expect these methods to allow for rapid library expansion and tuning of the amiloride scaffold for a range of RNA targets and for SOFAST NMR to allow unprecedented evaluation of small molecule:RNA interactions.

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Section: Resultsmentioning

confidence: 99%

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

et al. 2017

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“…The purpose of the present study was to characterize the pharmacological properties of the (radiolabeled) small-molecule CXCR3 antagonist VUF11211 from the piperazinyl-piperidine class, which contains many compounds possessing (sub)nanomolar affinities for CXCR3 (McGuinness et al, 2009;Kim et al, 2011;Shao et al, 2011;Nair et al, 2014). VUF11211 showed antagonistic behavior in CRE reporter gene-and b-arrestin recruitment assays, where it completely blocked CXCL11-induced receptor activation (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In view of the potential therapeutic interest in CXCR3 blockade in diseases like rheumatoid arthritis and allograft rejection (Wijtmans et al, 2011), many different drug discovery programs have yielded several distinct chemical classes of small-molecule compounds, including antagonists as well as a few agonists (Wijtmans et al, 2008(Wijtmans et al, , 2011, such as the 8-azaquinazolinone compounds from Amgen Inc. (AMG487, (R)-N- (1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-N-(pyridin-3-ylmethyl)-2-(4-trifluoromethoxy)phenyl)acetamide; Washington, D.C.) and Neurocrine Biosciences pyrimidin-2-yl)ethyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-N-(pyridin-3-ylmethyl)acetamide; San Diego, CA), which bind to CXCR3 with affinities in the nanomolar range (Heise et al, 2005;Johnson et al, 2007;Verzijl et al, 2008). Moreover, a piperazinyl-piperidine compound class containing ligands with nanomolar CXCR3 affinities was reported by Schering Plough (now Merck Sharp & Dohme, Kenilworth, NJ) (Mcguinness et al, 2009;Kim et al, 2011;Shao et al, 2011;Nair et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Characterization of [³H]VUF11211, a Novel Radiolabeled Small-Molecule Inverse Agonist for the Chemokine Receptor CXCR3

Scholten¹,

Custers²,

Stunnenberg³

et al. 2015

Mol Pharmacol

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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.

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“…These ligands are produced by the activated leukocytes (monocytes and macrophages), vascular endothelial cells and activated tissue cells [9] . CXCR3 and its ligands are found be highly expressed over a broad spectrum of diseases conditions like inflamed joints of rheumatoid arthritis patients [10] , multiple sclerosis lession in the brain [11] , asthma [12] , psoriasis [12] , tumor metastasis [13] , Type 1 diabetes [14] and in cardiac allograft rejection [15] . Thereby CXCR3 receptor's involvement over a wide range of diseases has made it to be an attractive therapeutic target of interest for the treatment of the above diseases.…”

Section: Introductionmentioning

confidence: 99%

Homology Modeling of Chemokine Receptor CXCR3: A Novel Therapeutic Target against Inflammatory Diseases

Shalini¹,

Madhavan²

2015

Journal of the Chosun Natural Science

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CXCR3 is a C-X-C chemokine receptor type 3 also known as GPR9 and CD183. CXCR3 is a G-Protein coupled chemokine receptor which interacts with three endogenous interferon inducible chemokine's (CXCL9, CXCL10 and CXCL11) and is proved to play a vital role in the Th1 inflammatory responses. CXCR3 has been implicated to be associated with various disease conditions like inflammatory diseases, autoimmune diseases, type I diabetes and acute cardiac allograft rejection. Therefore CXCR3 receptor is found to be an attractive therapeutic target for the treatment of inflammatory diseases. Inorder to decipher the biological function of a CXCR3, 3D structure is of much important but the crystal structure for CXCR3 has not yet been resolved. Hence, in the current study Homology modeling of CXCR3 was performed against various templates and validated using different parameters to suggest the best model for CXCR3. The reported best model can be used for further studies such as docking to identify the important binding site residues.

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III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl–piperazinyl–piperidine scaffold

Cited by 17 publications

References 13 publications

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

Pharmacological Characterization of [³H]VUF11211, a Novel Radiolabeled Small-Molecule Inverse Agonist for the Chemokine Receptor CXCR3

Homology Modeling of Chemokine Receptor CXCR3: A Novel Therapeutic Target against Inflammatory Diseases

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III. Identification of novel CXCR3 chemokine receptor antagonists with a pyrazinyl–piperazinyl–piperidine scaffold

Cited by 17 publications

References 13 publications

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

Amiloride as a new RNA-binding scaffold with activity against HIV-1 TAR

Pharmacological Characterization of [3H]VUF11211, a Novel Radiolabeled Small-Molecule Inverse Agonist for the Chemokine Receptor CXCR3

Homology Modeling of Chemokine Receptor CXCR3: A Novel Therapeutic Target against Inflammatory Diseases

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Pharmacological Characterization of [³H]VUF11211, a Novel Radiolabeled Small-Molecule Inverse Agonist for the Chemokine Receptor CXCR3