Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3

doi:10.1016/j.bmcl.2007.03.106

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 12, 15 June 2007, Pages 3339-3343

https://doi.org/10.1016/j.bmcl.2007.03.106 Get rights and content

Abstract

A series of quinazolinone-derived inhibitors of the CXCR3 receptor have been synthesized and their affinity for the receptor evaluated. Compounds were evaluated in a ¹²⁵I-IP10 displacement assay and in in vitro cell migration assays to IP10, ITAC, and MIG using human peripheral blood mononuclear cells.

Graphical abstract

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AMG487, a selective CXCR3 antagonist, is a small molecule that has entered clinical trials and it has exhibited efficacy in several pathological process [21,39]. Previous studies have confirmed that AMG487 possessed efficacy in lung inflammation, retinal dysfunction and cell loss [21,26]. In our recent study, we confirmed that AMG487 has potent anti-arthritic activity in CIA mice by regulating the number of Treg/T helper 17 (Th17) cells [6].
Rheumatoid arthritis (RA) is an autoimmune disease classified by uncontrolled joint inflammation leading to the destruction of both cartilage and joints. Despite progress made in RA treatment in the past decade, new drugs with high efficacy and fewer long-term adverse effects are still needed; thus, safe anti-inflammatory therapies for RA are urgently needed. Previous results demonstrated that the CXCR3 antagonist is an extremely attractive therapeutic target for the treatment of several autoimmune diseases, suggesting that it might have an inhibitory effect on RA. In this study, we investigated the effect of AMG487, a selective CXCR3 antagonist, on collagen-induced arthritis (CIA) in mice and evaluated its potential therapeutic mechanism. Following induction of CIA, mice were treated with AMG487 (5 mg/kg, intraperitoneally), to investigate their protective effects against CIA. CD4, CD25, CCR6, IL-9, NF-κB, IL-6, IL-17A, IL-21, STAT6 and Foxp3 expressing GITR⁺ and CD45⁺ cells were measured in the spleen using flow cytometry to assess anti-inflammatory effects of AMG487. The mRNA and protein expression of GITR, CCR6, IL-9, and IL-21 were measured using quantitative real-time PCR and western blot analysis in knee tissue. AMG487 significantly alleviated joint inflammation by decreasing GITR⁺CD25⁺, GITR⁺CD45⁺, GITR⁺IL-9⁺, GITR⁺NF-κB⁺ CD45⁺CD4⁺, CD45⁺CCR6⁺, CD45⁺IL-6⁺ cells, CD45⁺IL-17A⁺, and CD45⁺IL-21⁺, and increasing GITR⁺Foxp3⁺ and GITR⁺STAT6⁺ cells. There was a significant decrease in mRNA and protein expression of GITR, CD4, CCR6, IL-6, IL-9, and IL-21 in knee tissue of CIA mice. This study demonstrates that AMG487 has a potential therapeutic effect on RA and could explore novel anti-inflammatory therapies for its treatment.
CXCR3 antagonist AMG487 suppresses rheumatoid arthritis pathogenesis and progression by shifting the Th17/Treg cell balance
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Indeed, CXCR3-deficient mice show reduced arthritis symptoms [39]. AMG487 is a selective CXCR3 antagonist that exhibits biological activity in preclinical models of cellular recruitment [23,28]. At least two CXCR3 antagonists have shown efficacy in preclinical studies on inflammatory disease, and one CXCR3 antagonist has been assessed in clinical trials [7].
Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by uncontrolled joint inflammation and damage to bone and cartilage. Previous studies have shown that chemokine receptors have important roles in RA development, and that blocking these receptors effectively inhibits RA progression. Our study was undertaken to investigate the role of AMG487, a selective CXCR3 antagonist, in DBA/1J mice bearing collagen-induced arthritis (CIA). Following induction of CIA, animals were treated with 5 mg/kg AMG487 intraperitoneally every 48 h, starting from day 21 until day 41 and evaluated for clinical score, and histological hallmarks of arthritic inflammation. We further investigated the effect of AMG487 on Th1 (T-bet), Th17 (IL-17A, RORγt, STAT3), Th22 (IL-22), and T regulatory (Treg; Foxp3 and IL-10) cells in splenic CXCR3⁺ and CD4⁺ T cells using flow cytometry. We also assessed the effect of AMG487 on T-bet, RORγt, IL-17A, IL-22, Foxp3, and IL-10 at both mRNA and protein levels using RT-PCR and Western blot analyses of knee samples. The severity of clinical scores, and histological inflammatory damage decreased significantly in AMG487-treated compared with CIA control mice. Moreover, the percentage of Th1, Th17, and Th22 cells decreased significantly and that of Treg cells increased in AMG487-treated mice. We further observed that AMG487-treatment downregulated T-bet, IL-17A, RORγt, and IL-22, whereas it upregulated Foxp3 and IL-10 mRNA and protein levels. This study demonstrates the antiarthritic effects of AMG487 in CIA animal model and supports the development of CXCR3 antagonists as a novel strategy for the treatment of inflammatory and arthritic conditions.
Blocking CXCR3 with AMG487 ameliorates the blood-retinal barrier disruption in diabetic mice through anti-oxidative
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Oxidative stress and blood-retinal barrier (BRB) damage induced by hyperglycemia are the principal processes involved in the early stages of diabetic retinopathy (DR). CXC chemokine receptor 3 (CXCR3)-mediated inflammatory infiltration exists in many disease models. The main objective of the present study was to determine whether AMG487, a CXCR3 antagonist, can ameliorate BRB disruption and reactive oxygen species generation in the DR model. The retinal endothelial cell and ganglion cell ultrastructures were observed using a transmission electron microscope. The pericyte marker PDGFR-β, tight junction occludin, and leaking albumin were evaluated. The oxidative stress level, CCAAT-enhancer-binding protein homologous protein (CHOP), and p-p38 expression were also investigated in vivo and in vitro. The results indicated that AMG487 application might alleviate PDGFR-β and occludin loss, and decreased the residual content of retinal albumin in the streptozocin-induced DR mouse model via the inhibition of oxidative and endoplasmic reticulum stress, in which p38 activation was also involved. Thus, CXCR3 inhibition might be a target to prevent the early stage of DR injury.
CXCR3 blockade combined with cyclosporine A alleviates acute graft-versus-host disease by inhibiting alloreactive donor T cell responses in a murine model
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These results suggest that CXCR3 blockade may be an attractive strategy for aGVHD prophylaxis. AMG487 is a selective CXCR3 antagonist that exhibits good oral bioavailability and robust in vivo biological activity in a preclinical model of cellular recruitment (Johnson et al., 2007; Henne et al., 2012) and is the only CXCR3 antagonist that has been reported to be evaluated in clinical trials (Andrews and Cox, 2016). It can inhibit CXCR3-mediated cell migration by inhibiting the binding of chemokines CXCL9, CXCL10 and CXCL11 to CXCR3.
Chemotaxis of T cells to acute graft-versus-host disease (aGvHD) target tissues directed by chemokines and their receptors plays a key role in the pathogenesis of aGvHD. Blockade of lymphocyte migration by targeting chemokine receptors may be a viable strategy for the prevention and treatment of aGvHD, which is quite distinguishable from typical efforts to use immunosuppressive medications that have been associated with some side effects. CXCR3 and its ligands have been reported to be correlated with aGvHD pathogenesis. Using the small-molecule CXCR3 antagonist AMG487, we demonstrated that AMG487 combined with cyclosporine A (CsA) effectively alleviated aGvHD with a prolonged mean survival time and significantly inhibited the infiltration of inflammatory cells in aGvHD target tissues in a murine aGvHD model. In addition, AMG487 combined with CsA inhibited the activation, proliferation and differentiation of donor-derived T cells in the spleens. Further results showed that the concentrations of Th1 cells associated with pro-inflammatory cytokines such as IFN-γ and TNFα in serum were decreased. In addition, AMG487 treatment did not alter CXCR3 and CCR5 expression in donor-derived T cells but elevated the serum CXCL9 and CXCL10 levels. This novel and effective approach has the potential to develop a new clinical method to prevent and treat aGvHD.

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^†: Alan Huang, Gilead Sciences, Inc., Foster City, CA 94404; Andrew Marcus, University of California-Berkeley, Berkeley, CA 94720; Feng Xu, XenoPort Inc., Santa Clara, CA 94404; Jeff Kumer, Sunesis Pharmaceuticals Inc., South San Francisco, CA 94080; Chris Lawrence, Xencor, Monrovia, CA, 91016.

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Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3

Abstract

Graphical abstract

Clin. Immunol.

Ann. Rep. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

J. Clin. Invest.

J. Clin. Invest.

J. Immunol.

J. Invest. Dermatol.