Synthesis and structure–activity relationship of 3-phenyl-3H-quinazolin-4-one derivatives as CXCR3 chemokine receptor antagonists

Storelli, Stefania; Verdijk, Pauline; Verzijl, Dennis; Timmerman, Henk; Stolpe, Andrea C. van de; Tensen, Cornelis P.; Smit, Martine J.; Esch, Iwan J. P. de; Leurs, Rob

doi:10.1016/j.bmcl.2005.03.070

Cited by 29 publications

(22 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A selection of CXCR3-targeting small-molecule antagonists from two different structural classes were synthesized as described previously, and then they were subjected to detailed pharmacological analysis: quinazolinone-derived 3H-pyrido[2,3-d]pyrimidin-4-one compounds VUF10472 (NBI-74330) (Heise et al, 2005;Storelli et al, 2007) and VUF10085 (AMG 487) (Johnson et al, 2007;Storelli et al, 2007), the 3H-quinazolin-4-one VUF5834 (Storelli et al, 2005;Johnson et al, 2007), and the imidazolium compound VUF10132 (Axten et al, 2003) (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Synthesis of VUF5834 (Storelli et al, 2005), VUF10472, and VUF10085 (Storelli et al, 2007) has been described previously.…”

Section: Methodsmentioning

confidence: 99%

“…Several classes of small-molecule compounds targeting CXCR3 have recently been described, including 4-N-aryl-[1,4]diazepane ureas (Cole et al, 2006), 1-aryl-3-piperidin-4-yl-urea derivatives (Allen et al, 2007), quinazolin-4-one, 3H-pyrido [2,3-d]pyrimidin-4-one derivatives (Heise et al, 2005;Storelli et al, 2005;Johnson et al, 2007;Storelli et al, 2007), and the above-mentioned quaternary ammonium anilide TAK-779 (Gao et al, 2003). So far, no detailed information is available on the molecular mechanism of action of these small-molecule antagonists at the CXCR3 receptor, despite the general notion that small molecule ligands probably will not have overlapping binding sites with the chemokines, which are supposed to bind mainly to the N terminus and extracellular receptor loops (Murphy et al, 2000).…”

mentioning

confidence: 99%

“…In this study, we report on the molecular characterization of the 3H-pyrido [2,3-d]pyrimidin-4-one derivatives VUF10472 (NBI-74330) (Heise et al, 2005;Storelli et al, 2007) and VUF10085 (Johnson et al, 2007;Storelli et al, 2007); the 3H-quinazolin-4-one VUF5834 (Storelli et al, 2005;Johnson et al, 2007); the imidazolium compound VUF10132 (Axten et al, 2003); and the quaternary ammonium anilide TAK-779 (Baba et al, 1999) at CXCR3 of human (Loetscher et al, 1996), rat (Wang et al, 2000), and mouse (Tamaru et al, 1998;Lu et al, 1999). In addition, CXCR3 from rhesus macaque was cloned, characterized, and subjected to a detailed pharmacological analysis using the nonpeptidergic compounds.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Noncompetitive Antagonism and Inverse Agonism as Mechanism of Action of Nonpeptidergic Antagonists at Primate and Rodent CXCR3 Chemokine Receptors

Verzijl

Storelli

Scholten

et al. 2008

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

The chemokine receptor CXCR3 is involved in various inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, and allograft rejection in transplantation patients. The CXCR3 ligands CXCL9, CXCL10, and CXCL11 are expressed at sites of inflammation, and they attract CXCR3-bearing lymphocytes, thus contributing to the inflammatory process. In this study, we characterize five nonpeptidergic compounds of different chemical classes that block the action of CXCL10 and CXCL11 at the human CXCR3, i.e., the 3H-pyrido[2,3-d]pyrimidin-4-one derivatives N-1R- [3-(4-et-

show abstract

Section: Resultsmentioning

confidence: 99%

“…Synthesis of VUF5834 (Storelli et al, 2005), VUF10472, and VUF10085 (Storelli et al, 2007) has been described previously.…”

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Noncompetitive Antagonism and Inverse Agonism as Mechanism of Action of Nonpeptidergic Antagonists at Primate and Rodent CXCR3 Chemokine Receptors

Verzijl

Storelli

Scholten

et al. 2008

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…The electron-withdrawing character of the trifluoromethyl moiety is also an important determinant for ligand affinity (.100-fold better over unsubstituted benzyl) (Storelli et al, 2005(Storelli et al, , 2007. Polar aromatic interactions between CXCR3 and NBI-74330 are identified by F131 3.32 A, Y271 6.51 A, and Y308 7.43 A, reducing affinity by 10-, 6-, and 30-fold, respectively (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Therapeutic Targeting of the CXCR3 Receptor

Esch

Leurs

2010

Methods and Principles in Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

A search for T lymphocyte-specific chemokine receptors led to the discovery of the CXCR3 receptor in 1996. A novel cDNA was isolated from a human CD4 þ T cell library and the encoded GPCR proved to have affinity for chemokines [1]. Further work revealed that CXCR3 consists of 368 amino acids which assemble in a typical seven-transmembrane a-helical architecture. Chapter 2 has described in detail the structural characteristics of the chemokine receptor family and CXCR3 fits this general picture. CXCR3 exhibits typical structural motifs for GPCRs, such as the conserved DRY motif, the NPxxYx 5,6 F motif and cysteine residues in the first and second extracellular loops [2]. Also, like most chemokine receptors, CXCR3 has additional cysteine residues in the N-terminus and third extracellular loop. The threonine and serine residues in the intracellular C-terminal tail are potential sites for phosphorylation by receptor-or second messenger-regulated kinases [1, 3].CXCR3 receptors are found on activated Th1 lymphocytes, blood T cells and on a small proportion of B cells and natural killer cells [1,4,5]. CXCR3 signaling occurs preferably through pertussis toxin-sensitive Ga i proteins and involves several downstream processes such as mediation of chemotaxis, induction of calcium flux and activation of kinases such as p44/p42 MAPK and Akt [1, 3,6]. The endogenous agonists for CXCR3 are CXC chemokines CXCL9, CXCL10 and CXCL11, which were traditionally called Mig, IP-10 and I-TAC/IP-9, respectively [1, 7-10]. Of these, CXCL11 has the highest potency and efficacy on CXCR3 [1,[7][8][9][10][11]. Several reports exist on the interaction of other CXCL chemokines with CXCR3, most notably CXCL13 [12] and CXCL4 [13]. Generally, a chemokine is considered to bind to the N-terminus and extracellular loops of a chemokine receptor. Activation is thought to occur through interaction of the N-terminus of the chemokine with the transmembrane domains of the receptor [14,15]. Indeed, manipulations at the N-terminal amino acids of CXCL10 or CXCL11 can change it from a CXCR3 agonist into a CXCR3 antagonist [16][17][18][19].

show abstract

Synthesis and structure–activity relationship of 3-phenyl-3H-quinazolin-4-one derivatives as CXCR3 chemokine receptor antagonists

Cited by 29 publications

References 23 publications

Noncompetitive Antagonism and Inverse Agonism as Mechanism of Action of Nonpeptidergic Antagonists at Primate and Rodent CXCR3 Chemokine Receptors

Noncompetitive Antagonism and Inverse Agonism as Mechanism of Action of Nonpeptidergic Antagonists at Primate and Rodent CXCR3 Chemokine Receptors

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

Therapeutic Targeting of the CXCR3 Receptor

Contact Info

Product

Resources

About