Identification and structure–activity relationships of 1-aryl-3-piperidin-4-yl-urea derivatives as CXCR3 receptor antagonists

Allen, Daniel R.; Bolt, A.H.; Chapman, Gayle A.; Knight, Roland L.; Meissner, Johannes; Owen, David A.; Watson, Robert J.

doi:10.1016/j.bmcl.2006.10.088

Cited by 34 publications

(16 citation statements)

References 17 publications

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“…After the recognition of CXCR3 as a potential attractive drug target, several small-molecule CXCR3 antagonists have recently been identified (Gao et al, 2003;Heise et al, 2005;Storelli et al, 2005;Cole et al, 2006;Allen et al, 2007;Johnson et al, 2007;Storelli et al, 2007). In this study, we selected five nonpeptidergic antagonists from four different structural classes, and we studied their mechanism of action at the human CXCR3.…”

Section: Discussionmentioning

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).…”

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confidence: 99%

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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

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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-

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

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“…[102] Replacement of the cyclooctenyl ring by a variety of highly lipophilic substituents mostly afforded K i values higher than 10 mm. A fortunate exception was the naturally occurring (À)myrtenyl group which gave a compound with affinity similar to 26.…”

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confidence: 99%

“…A fortunate exception was the naturally occurring (À)myrtenyl group which gave a compound with affinity similar to 26. [102] With the (À)myrtenyl group in place, extensive structural variation of the aromatic group was performed to optimise affinity and druglike properties. Several compounds were identified that had better affinities ([ ).…”

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Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

et al. 2008

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The CXCR3 chemokine receptor was first discovered in 1996 and has been shown to play an important role in several diseases, most of which are related to inflammation. This review describes in detail the development of small CXCR3 ligands and their therapeutic potential. Classes of CXCR3 antagonists with strikingly variable core structures have emerged. Some of these compounds have confirmed the beneficial role of CXCR3 antagonism in animal models of disease. One of the compounds, AMG487, progressed to Phase II clinical trials but has been withdrawn because of lack of efficacy. New antagonist classes are being developed to reveal the full therapeutic potential of CXCR3.

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Therapeutic Targeting of the CXCR3 Receptor

Esch

Leurs

2010

Methods and Principles in Medicinal Chemistry

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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].

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Identification and structure–activity relationships of 1-aryl-3-piperidin-4-yl-urea derivatives as CXCR3 receptor antagonists

Cited by 34 publications

References 17 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

Towards Small‐Molecule CXCR3 Ligands with Clinical Potential

Therapeutic Targeting of the CXCR3 Receptor

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