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A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.

Jenh CH, Cox MA, Cui L, Reich EP, Sullivan L, Chen SC, Kinsley D, Qian S, Kim SH, Rosenblum S, Kozlowski J, Fine JS, Zavodny PJ, Lundell D - BMC Immunol. (2012)

Bottom Line: SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models.Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.It is efficacious in multiple preclinical disease models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Respiratory and Immunology, Merck Research Laboratories, Kenilworth, NJ 07033, USA. chungherjenh@yahoo.com.

ABSTRACT

Background: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.

Results: In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.

Conclusions: SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.

No MeSH data available.


Related in: MedlinePlus

Plasma concentration versus time profiles of SCH 546738 in Lewis rat and C57BL/6 mouse. SCH 546738 in 0.4% methylcellulose was administered orally at 10 mg/kg (mpk) in Lewis rats or 30 mpk in C57BL/6 mice. The plasma concentration of SCH 546738 in the blood was calculated as the mean of 3 animals (n = 3) at indicated time points post-dose. Their AUC from 0 to 24 hr is also calculated and indicated.
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Figure 4: Plasma concentration versus time profiles of SCH 546738 in Lewis rat and C57BL/6 mouse. SCH 546738 in 0.4% methylcellulose was administered orally at 10 mg/kg (mpk) in Lewis rats or 30 mpk in C57BL/6 mice. The plasma concentration of SCH 546738 in the blood was calculated as the mean of 3 animals (n = 3) at indicated time points post-dose. Their AUC from 0 to 24 hr is also calculated and indicated.

Mentions: SCH 546738 was tested at concentrations of 1-10 μM against a panel of 49 GPCR binding assays. Most of the assays were not affected by SCH 546738 (Table 2). These results indicate that SCH 546738 is a highly selective antagonist of CXCR3. In addition, SCH 546738 has a favourable pharmacokinetic profile in rodents. Figure 4 shows the plasma concentrations of SCH 546738 in Lewis rat and C57BL/6 mouse over 24 hr post-dose. The AUC (0-24 hr) is 7.7 μM.hr in Lewis rat @ 10 mg/kg (mpk) and is 12.6 μM.hr in C57BL/6 mouse @ 30 mpk. Therefore, SCH 546738 is suitable for in vivo preclinical studies.


A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.

Jenh CH, Cox MA, Cui L, Reich EP, Sullivan L, Chen SC, Kinsley D, Qian S, Kim SH, Rosenblum S, Kozlowski J, Fine JS, Zavodny PJ, Lundell D - BMC Immunol. (2012)

Plasma concentration versus time profiles of SCH 546738 in Lewis rat and C57BL/6 mouse. SCH 546738 in 0.4% methylcellulose was administered orally at 10 mg/kg (mpk) in Lewis rats or 30 mpk in C57BL/6 mice. The plasma concentration of SCH 546738 in the blood was calculated as the mean of 3 animals (n = 3) at indicated time points post-dose. Their AUC from 0 to 24 hr is also calculated and indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3298469&req=5

Figure 4: Plasma concentration versus time profiles of SCH 546738 in Lewis rat and C57BL/6 mouse. SCH 546738 in 0.4% methylcellulose was administered orally at 10 mg/kg (mpk) in Lewis rats or 30 mpk in C57BL/6 mice. The plasma concentration of SCH 546738 in the blood was calculated as the mean of 3 animals (n = 3) at indicated time points post-dose. Their AUC from 0 to 24 hr is also calculated and indicated.
Mentions: SCH 546738 was tested at concentrations of 1-10 μM against a panel of 49 GPCR binding assays. Most of the assays were not affected by SCH 546738 (Table 2). These results indicate that SCH 546738 is a highly selective antagonist of CXCR3. In addition, SCH 546738 has a favourable pharmacokinetic profile in rodents. Figure 4 shows the plasma concentrations of SCH 546738 in Lewis rat and C57BL/6 mouse over 24 hr post-dose. The AUC (0-24 hr) is 7.7 μM.hr in Lewis rat @ 10 mg/kg (mpk) and is 12.6 μM.hr in C57BL/6 mouse @ 30 mpk. Therefore, SCH 546738 is suitable for in vivo preclinical studies.

Bottom Line: SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models.Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.It is efficacious in multiple preclinical disease models.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Respiratory and Immunology, Merck Research Laboratories, Kenilworth, NJ 07033, USA. chungherjenh@yahoo.com.

ABSTRACT

Background: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.

Results: In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.

Conclusions: SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.

No MeSH data available.


Related in: MedlinePlus