Therapeutic Targeting of the CXCR3 Receptor

Abstract

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].

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

“…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).…”

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

“…Overexpression of the CXCR3 receptor and/or its ligands (CXCL9, CXCL10, CXCL11) is often observed in rheumatoid arthritis and transplant rejection (Lacotte et al, 2009). In the past decade, many efforts have focused on the discovery of small molecule CXCR3 antagonists, leading to the disclosure of ligands with a multitude of different chemotypes (Wijtmans et al, 2008(Wijtmans et al, , 2010 …”

Several down, a few to go: histamine H3receptor ligands making the final push towards the market?

“…Besides the distribution in the CNS, H 3 R is present in the PNS as well, including the cardiovascular system, the airways and the gastrointestinal tract [13]. Over the years, several lines of evidence have suggested that H 3 R might be a therapeutic target in cognitive disorders, including attention deficit hyperactivity disorder (ADHD), Alzheimer's disease (AD) and schizophrenia, as well as in other therapeutic areas such as sleep disorders, pain, obesity and allergic rhinitis [14][15][16].…”

“…Vast amounts of literature on H 3 R receptor ligands have been published and they have been described in a number of recent reviews [4,14,15,[33][34][35]. A key theme in the development of these ligands was to provide the means to capitalize on therapeutic promise of H 3 R, both through tool compounds as well as through advanced drug candidates.…”

“…In a 2007 review, we described H 3 R ligands as breaking ground in a remarkable plethora of therapeutic areas [14] Figure 2). The discovery and clinical status of Pitolisant has recently been extensively described by Schwartz [39].…”