II. SAR studies of pyridyl–piperazinyl-piperidine derivatives as CXCR3 chemokine antagonists

Shao, Yinming; Anilkumar, G.; Carroll, Carolyn DiIanni; Dong, Guizhen; Hall, Jeremy L.; Hobbs, Doug W.; Jiang, Yunlei; Jenh, Chung‐Her; Kim, Seong Heon; Kozlowski, Joseph A.; McGuinness, Brian; Rosenblum, Stuart B.; Schulman, Inna; Shih, Neng‐Yang; Shu, Youheng; Wong, Michael; Yu, Wei; Zawacki, Lisa Guise; Zeng, Qingbei

doi:10.1016/j.bmcl.2010.12.114

Cited by 20 publications

(24 citation statements)

References 23 publications

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“…4A) . Rigidification of the benzyl moiety either by ring closure or intramolecular hydrogen bonding, at the cost of basicity, could maintain ligand affinity, indicating the importance of directionality for the chlorobenzyl moiety Shao et al, 2011). In the proposed binding mode, the chlorobenzyl moiety resides in a small space between TM4 and TM5 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…4, A, C, and E). The importance of the S-ethyl moiety on the piperazine core was proven by various substitutions that showed a preference for a small apolar group over larger or polar moieties (McGuinness et al, 2009;Shao et al, 2011). This implies that rotation of the pyridine and the piperidine rings with respect to the piperazine ring are restricted and that there is limited space around the ethyl moiety.…”

Section: Discussionmentioning

confidence: 99%

“…VUF11211 [compound 18i in the study by Shao et al (2011)] was synthesized in enantiopure form in our group according to the general synthetic procedures patented by Merck (McGuinness et al, 2006). Details of the synthetic procedures are Fig.…”

Section: Methodsmentioning

confidence: 99%

“…AMG487 was even assessed in clinical trials for treatment of psoriasis, but was discontinued after a phase IIa trial ). Moreover, a piperazinyl-piperidine compound class with high-affinity CXCR3 ligands has been disclosed by Schering-Plough (now Merck Sharp & Dohme, Whitehouse Station, NJ) (McGuinness et al, 2006(McGuinness et al, , 2009Shao et al, 2011). This compound series is effective in rodent models of CXCR3-associated disease, including transplant rejection and rheumatoid arthritis (Jenh et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

Scholten¹,

Roumen²,

Verkade-Vreeker³

et al. 2013

Mol Pharmacol

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CXC chemokine receptor CXCR3 and/or its main three ligands CXCL9, CXCL10, and CXCL11 are highly upregulated in a variety of diseases. As such, considerable efforts have been made to develop small-molecule receptor CXCR3 antagonists, yielding distinct chemical classes of antagonists blocking binding and/or function of CXCR3 chemokines. Although it is suggested that these compounds bind in an allosteric fashion, thus far no evidence has been provided regarding the molecular details of their interaction with CXCR3. Using site-directed mutagenesis complemented with in silico homology modeling, we report the binding modes of two high-affinity CXCR3 antagonists of distinct chemotypes: Here we show that NBI-74330 is anchored in the transmembrane minor pocket lined by helices 2 (W2.60, D2.63), 3 (F3.32), and 7 (S7.39, Y7.43), whereas VUF11211 extends from the minor pocket into the major pocket of the transmembrane domains, located between residues in helices 1 (Y1.39), 2 (W2.60), 3 (F3.32), 4 (D4.60), 6 (Y6.51), and 7 (S7.39, Y7.43). Mutation of these residues did not affect CXCL11 binding significantly, confirming the allosteric nature of the interaction of these small molecules with CXCR3. Moreover, the model derived from our in silico-guided studies fits well with the already published structure-activity relationship data on these ligands. Altogether, in this study, we show overlapping, yet different binding sites for two high-affinity CXCR3 antagonists, which offer new opportunities for the structure-based design of allosteric modulators for CXCR3.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

Scholten¹,

Roumen²,

Verkade-Vreeker³

et al. 2013

Mol Pharmacol

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“…CXCR3 is found to be predominantly expressed on activated T-cells of type1 (Th1) and it helps in activation and recruitment of Th1 cells [3][4][5] . In the recent studies it's been reported that CXCR3 is also found to be expressed on NK cells, B cells and partially on circulating CD4+ and CD8+ T cells [6] .…”

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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Amination of 2‐Pyridinesulfonic and 8‐Quinolinesulfonic Acids with Magnesium Amides

2019

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The amination of 2‐pyridine‐ and 8‐quinolinesulfonic acids using magnesium amides of the type R2NMgCl·LiCl is reported. Thus, several cyclic and acyclic amines were converted into the corresponding amides using iPrMgCl·LiCl, which reacted readily with sulfonic acids to produce aminopyridines and aminoquinolines. Various amines which are attractive in drug chemistry were suitable for this transformation.

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II. SAR studies of pyridyl–piperazinyl-piperidine derivatives as CXCR3 chemokine antagonists

Cited by 20 publications

References 23 publications

Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

Identification of Overlapping but Differential Binding Sites for the High-Affinity CXCR3 Antagonists NBI-74330 and VUF11211

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

Amination of 2‐Pyridinesulfonic and 8‐Quinolinesulfonic Acids with Magnesium Amides

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