Design, Synthesis, and Anti-Inflammatory Evaluation of a Novel PPARδ Agonist with a 4-(1-Pyrrolidinyl)piperidine Structure.

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a pharmaceutical target to treat metabolic diseases including atherosclerosis, but there is no PPARδ agonist available for clinical use. We have previously reported the discovery of piperidinyl/piperazinyl benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening methods. In the present study, we found that introduction of a pyrrolidine group into the 4-position of their central piperidine rings enhances hPPARδ activity and subtype selectivity. This led to the discovery of 21 having strong PPARδ agonist activity (EC50 = 3.6 nM) with excellent ADME properties. Furthermore, 21 significantly suppressed atherosclerosis progression by 50-60% with reduction of the serum level of MCP-1 in LDLr-KO mice.

Discovery and structure-activity relationship study of 2-piperazinyl-benzothiazole derivatives as potent and selective PPARδ agonists.

Peroxisome proliferator-activated receptor δ (PPARδ) is considered to be a target for treating metabolic syndrome, whereas there is no PPARδ agonist in clinical use. Previously, we have reported the discovery of 2-(1-piperidinyl)-1,3-benzothiazole derivatives as a new series of PPARδ agonists using docking-based virtual screening techniques. In this study, we performed the further optimization study of the lead compound 1 focusing on improvement of hydrophobic interactions in the binding site to enhance agonist efficacy for PPARδ and subtype selectivity, thereby discovering a novel PPARδ agonist 5g which exhibited high in vitro agonist activity (hPPARδ, EC50 = 4.1 nM) and sufficiently high selectivity ratio over PPARα and PPARγ. Moreover, 5g revealed a significant upregulation of high-density lipoprotein cholesterol level in vivo.

Discovery and structure-based design of a new series of potent and selective PPARδ agonists utilizing a virtual screening method.

Novel PPARδ agonists, 2-(1-piperidinyl)-1,3-benzothiazole derivatives were discovered by our proprietary docking-based virtual screening technique. Compound 1 as the initial hit was effectively modified to acquire PPARδ agonist activity, resulting in the discovery of compound 12 with high agonistic potency for PPARδ and selectivity over PPARα and PPARγ. Compound 12 also had good ADME profiles and showed in vivo efficacy as a lead.

Pathophysiological roles of nuclear factor kappaB (NF-kB) in pulmonary arterial hypertension: effects of synthetic selective NF-kB inhibitor IMD-0354.

AIMS: Proliferation of pulmonary arterial smooth muscle cells (PASMCs) is one histological sign of pulmonary arterial hypertension (PAH). We hypothesized that a signalling cascade from fibroblast growth factor 2 (FGF2) to plasminogen activator inhibitor 1 (PAI-1) and monocyte chemotactic protein-1 (MCP-1) via nuclear transcription factor nuclear factor kappaB (NF-kB) play a critical role in progression of PAH, and tested this hypothesis both in vivo and in vitro using a synthetic selective NF-kB inhibitor, N-(3,5-Bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide (IMD-0354). METHODS AND RESULTS: Monocrotaline (MCT) was injected into 75 Sprague-Dawley rats. Starting at day 14 after MCT injection, we administered IMD-0354 (MCT + IMD group) or vehicle (MCT group) daily. At day 32, 65% of the MCT + IMD group were alive compared with 0% of the MCT group. IMD-0354 prevented increase of right ventricular pressure, and suppressed proliferation and induced apoptosis of PASMCs. mRNA transcript levels of FGF2, PAI-1, and tissue plasminogen activator (t-PA) were lower in MCT + IMD compared with MCT. In in vitro experiments, IMD-0354 inhibited p65 translocation to the nucleus promoted by FGF2 in PASMCs. Furthermore, the time courses of extracellular signal-regulated kinase (Erk) 1/2, MCP-1, and PAI-1 stimulated with FGF2 were each markedly shortened by IMD-0354. CONCLUSIONS: We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF2-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.

An IκB kinase 2 inhibitor IMD-0354 suppresses the survival of adult T-cell leukemia cells.

Adult T-cell leukemia (ATL) is a fatal T-cell malignancy associated with human T-cell leukemia virus type I infection. The aberrant expression of nuclear factor-κB (NF-κB) is considered to contribute to the malignant phenotype and chemo-resistance of ATL cells. Because of the poor prognosis of ATL, the development of new therapeutic strategies is direly needed. In the present study, we show that an IκB kinase 2 (IKK2) inhibitor, IMD-0354, efficiently inhibits the survival of CD4(+) CD25(+) primary ATL cells and prevents the growth of or induces apoptosis of patient-derived ATL cell lines. Assays of transcription with integrated forms of reporter genes revealed that IMD-0354 suppresses NF-κB-dependent transcriptional activity. Moreover, the daily administration of IMD-0354 prevents the growth of tumors in mice inoculated with ATL cells. Our results suggest that targeting IKK2 with a small molecule inhibitor, such as IMD-0354, is an attractive strategy for the treatment of ATL.

Effects of pharmacological suppression of plasminogen activator inhibitor-1 in myocardial remodeling after ischemia reperfusion injury.

Plasminogen activator inhibitor-1 (PAI-1) contributes to cardiac ventricular remodeling because migration of inflammatory cells and attenuation of extracellular matrix degradation are caused by plasmin and matrix metalloproteinase. However, the roles of PAI-1 in myocardial ischemia reperfusion (I/R) injury and the following inflammatory response have not yet been well elucidated. To clarify the role of PAI-1 in myocardial I/R injury, we used a specific PAI-1 inhibitor (IMD-1622) in a rat model. The left anterior descending coronary artery was ligated and reperfusion was performed by loosening the suture after 30 minutes of arterial occlusion. A single administration of IMD-1622 (20 mg/kg) or vehicle was given intraperitoneally and then the rats were sacrificed on day 1 or day 14 after I/R. Blood pressure, echocardiograms, histopathology, and molecular examination were performed. The examinations revealed that PAI-1 inhibitor showed limited effects on cardiac dysfunction and ventricular remodeling after I/R. We conclude that the pharmacological inhibition of PAI-1 may not affect ventricular remodeling after myocardial I/R injury.

The effects of pharmacologic plasminogen activator inhibitor-1 inhibition in acute and chronic rejection in murine cardiac allografts.

BACKGROUND: Acute rejection and graft arterial disease (GAD) in cardiac transplantation limit the long-term survival of recipients; these processes are enhanced by inflammation and thrombus formation. Plasminogen activator inhibitor (PAI)-1 is critical in the inflammation and thrombus formation. However, little is known about the effect of PAI-1 in heart transplantation. Thus, the objective was to clarify the role of PAI-1 in the progression of cardiac rejection. METHODS: Murine hearts were heterotopically transplanted using major mismatch combinations for evaluation of acute rejection and class II mismatch combinations for the GAD. We administered the specific PAI-1 inhibitor (IMD-1622) into murine recipients after cardiac allografts. RESULTS: Nontreated allografts of the major mismatch group were acutely rejected, whereas the PAI-1 inhibitor prolonged their survival. Although severe cell infiltration and intimal thickening with enhancement of inflammatory factors were observed in untreated allografts of class II mismatch group on day 60, the PAI-1 inhibitor attenuated these changes. CONCLUSION: The PAI-1 inhibitor is potent for the suppression of both acute rejection and GAD.

Novel IkB kinase inhibitors for treatment of nuclear factor-kB-related diseases.

INTRODUCTION: NF-kB is a key regulator of inflammation and immunity in cancer development. The IkB kinase (IKK) is a multisubunit complex containing catalytic subunits termed IKK-α, -ß and -γ. It is well known that many pro-inflammatory stimuli require the IKK-ß subunit for NF-kB activation. AREAS COVERED: NF-kB affects the progression of inflammation-related diseases,such as myocardial ischemia, bronchial asthma, arthritis, cancer and other diseases. We review the characteristics and effects of these inhibitors on inflammatory and other diseases. EXPERT OPINION: Various synthesized IKK inhibitors have been developed and they will be used clinically in the near future.

Effects of specific chemical suppressors of plasminogen activator inhibitor-1 in cardiovascular diseases.

INTRODUCTION: plasminogen activator inhibitor-1 (PAI-1) is critical in thrombus formation and inflammation. Although these are essential pathological features of cardiovascular diseases, the effects of PAI-1 inhibition against the development of cardiovascular remodeling have not been well studied. AREAS COVERED: the review explores the therapeutic value of PAI-1 in the progression of various cardiovascular diseases. To date, the authors have reported that a novel PAI-1 inhibitor suppressed the development of experimental autoimmune myocarditis, vascular remodeling after arterial injury, and heart transplant rejection using rodent models. Pathologically, the PAI-1 inhibitor improved histological remodeling of myocardium and arteries with suppression of inflammation and thrombus formation. EXPERT OPINION: PAI-1 inhibitors appear to exhibit potent effects on the prevention of adverse tissue remodeling. However, PAI-1 is a multifunctional protein and more research is needed to further elucidate the association between PAI-1 expression and cardiovascular disease.

Aldosterone-induced kidney injury is mediated by NFκB activation.

BACKGROUND: Aldosterone induces inflammation and fibrosis in the kidney, while nuclear factor κB (NFκB) plays key roles in inflammation mediated by various cytokines. Here, we determined the roles of NFκB activation in aldosterone-induced kidney injury. METHODS: We used unilaterally nephrectomized rats with or without continuous aldosterone infusion and 0.9% saline as drinking water for 3 weeks. IMD-1041, an IKKß inhibitor, and spironolactone were orally administered to inhibit NFκB and mineralocorticoid receptor, respectively. RESULTS: The aldosterone-infused rats exhibited severe kidney injury, hypertension, and increased expression of pro-inflammatory and fibrotic proteins, osteopontin, fibrinogen, collagen type I, and PAI-1. Western blotting confirmed NFκB activation by aldosterone by the increased amount of p65 in the nuclear fraction of the kidney, and oral IMD-1041 prevented the kidney injury and lessened the increase in pro-inflammatory and fibrotic proteins without significant changes in blood pressures. In addition, changes in angiotensin-converting enzyme 2 (ACE2), which has been found to act as a protective factor in various kidney injury models, were examined. Immunofluorescence studies revealed the presence of ACE2 in the brush-border membrane of the proximal convoluted tubules and markedly blunted ACE2 staining in aldosterone-infused rats. The decrease in amount of ACE2 protein was confirmed by Western blotting, and IMD-1041 also prevented the decrease in ACE2. The administration of spironolactone also abolished the effects of aldosterone. CONCLUSION: Our results suggest that aldosterone induces kidney injury via activation of NFκB and mineralocorticoid receptor, and that decreased ACE2 expression may play an important role in aldosterone-induced kidney injury.

Effectiveness of IkappaB kinase inhibitors in murine colitis-associated tumorigenesis.

PURPOSE: Nuclear factor kappaB (NF-kappaB) activation is involved in various inflammatory illnesses, for example inflammatory bowel disease, and is thought to be a key factor in the tumor-promoting mechanism of inflammation-associated tumorigenesis. This study investigated whether inhibitors of IKKbeta, which is a critical kinase for NF-kappaB activation, reduce colitis-associated tumorigenesis in mice. METHODS: We used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. Effects of IKKbeta inhibitors, NBD peptide, and IMD-0354 were examined. RESULTS: In a colitis-associated cancer model, treatment with the IKKbeta inhibitors NBD peptide and IMD-0354 significantly reduced the number of tumors compared with the untreated group. The tumors were also significantly smaller in the inhibitor-treated mice than in the untreated mice. Macrophage and neutrophil infiltration decreased with the inhibitor treatment. NF-kappaB activation and the expression of Cox-2 and iNOS were observed in tumor tissues, and the inhibitors ameliorated their expression. These inhibitors blocked NF-kappaB activation and the expression of proinflammatory cytokines mediated by the culture supernatant of inflamed colon in murine primary macrophages. In-vitro and in-vivo experiments showed that these drugs, especially NBD peptide, could also inhibit the proliferation of colonic epithelial cells. CONCLUSION: These results imply that IKKbeta-targeted NF-kappaB blockade is an attractive therapeutic approach for the prevention of colitis-associated tumors.

Antiallergic and anti-inflammatory effects of a novel I kappaB kinase beta inhibitor, IMD-0354, in a mouse model of allergic inflammation.

BACKGROUND: Nuclear factor (NF)-kappaB is a transcription factor known to regulate allergy-associated cytokine and chemokine production related to the induction of inflammation. I kappaB kinase beta (IKK beta), which is responsible for activation of the NF-kappaB pathway, may be an ideal molecular target to inhibit this process. IMD-0354 [N-(3,5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide] is an attractive novel IKK beta inhibitor that prevents the production of inflammatory cytokines in various diseases, although it is not known if IMD-0354 is effective against allergic inflammation. This study aimed to elucidate the antiallergic effects of a newly synthesized IKK beta inhibitor, IMD-0354, in a mouse model of allergic inflammation. METHODS: We generated ovalbumin (OVA)-sensitized mice which were then challenged with OVA. IMD-0354 was administered intraperitoneally to therapeutic groups. Lung histopathology and the concentrations of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) and supernatants of lung homogenates were determined. RESULTS: Administration of IMD-0354 ameliorated airway hyperresponsiveness and reduced the numbers of bronchial eosinophils and mucus-producing cells in OVA-sensitized mice. The total numbers of cells and eosinophils in BALF were also reduced by treatment with IMD-0354. Treatment with IMD-0354 inhibited the production of Th2 cytokines such as interleukin (IL)-5 and IL-13 and eotaxin in the airways and/or lungs of OVA-sensitized mice, but it did not affect the restoration of Th1 cytokines such as IL-12 and interferon-gamma under the same experimental conditions. IgE production was also inhibited by IMD-0354. CONCLUSION: A specific IKK beta inhibitor, IMD-0354, improved allergic airway inflammation and hyperresponsiveness in mice. IMD-0354 may have therapeutic potential for bronchial asthma.

A novel IKK inhibitor suppresses heart failure and chronic remodeling after myocardial ischemia via MMP alteration.

OBJECTIVE: Amplification of inflammatory response in the non-infarct area plays an important role in the pathogenesis of ventricular remodeling after myocardial ischemia. Activation of nuclear factor-kappa B (NF-kappaB) is involved in this amplification through a positive feedback loop of pro- inflammatory cytokines. We investigated the efficacy of IKK blockade with IMD-0560, a novel inhibitor of IKK, in a rat myocardial ischemia model. METHODS/RESULTS: Left coronary artery occlusion (28 days) was carried out in Sprague-Dawley rats. Daily intraperitoneal injections of IMD-0560 (5 mg/kg) were done after the operation. Treatment with IMD-0560 significantly improved cardiac function as indicated by the preservation of fractional shortening and lower serum brain natriuretic peptide level. Histological analysis showed that IMD-0560 treatment suppressed thinning in the infarcted area compared with vehicle-treated hearts. Moreover, in situ zymography showed matrix metalloprotease-9 activity was inhibited in the infarct area. CONCLUSION: We revealed that the IKK blockade is potent for the suppression of chronic ventricular remodeling after myocardial ischemia.

A specific inhibitor of plasminogen activator inhibitor-1 suppresses rat autoimmune myocarditis.

OBJECTIVE: Myocarditis is a serious disease, however no effective treatment exists. Plasminogen activator inhibitor-1 (PAI-1) is critical in cell recruitment and inflammation. Although inflammation is an essential pathological feature of acute myocarditis, the effects of PAI-1 inhibition on the development of acute myocarditis have not been well studied. METHODS: To clarify the role of PAI-1, we used a rat experimental autoimmune myocarditis (EAM) model. Lewis rats were immunized on day 0 with porcine cardiac myosin to establish EAM. The rats with induced EAM were treated with the PAI-1 inhibitor (IMD-1622) (n = 8) or not treated (n = 6); hearts were harvested on day 21. Echocardiograms, heart weight to body weight ratios (H:B), histological examinations and in vitro studies were performed. RESULTS: Echocardiograms indicated that the PAI-1 inhibitor improved left ventricular fractional shortening (50 +/- 3%) compared with controls (36 +/- 4%, p < 0.05). The inhibitor significantly reduced H:B ratios compared with controls. Pathologically, areas of myocardial cell infiltration and fibrosis in the inhibitor-treated group were significantly smaller than those in the control group. Immunohistochemistry revealed enhanced expression of adhesion molecules and inflammatory factors in non-treated EAM hearts, the inhibitor suppressed this expression. CONCLUSIONS: The PAI-1 inhibitor suppressed EAM development; thus this inhibitor is promising for treating clinical myocarditis.

The effects of pharmacological PAI-1 inhibition on thrombus formation and neointima formation after arterial injury.

OBJECTIVE: Plasminogen activator inhibitor (PAI)-1 plays a role in neointimal formation after percutaneous coronary intervention (PCI), the effect of overexpression or lack of PAI-1 is controversial. Murine arterial injury models develop neointimal hyperplasia similar to that observed in clinical coronary arterial restenosis after PCI. METHODS AND RESULTS: To clarify the role of PAI-1 in thrombus formation and neointimal formation after arterial injury, we used a specific PAI-1 inhibitor (IMD-1622) in a rat aorta-vein shunt model and a mouse arterial injury model. While the non-treated shunt model showed massive thrombus formation, IMD-1622 administration suppressed this. Injured arteries with vehicles showed significant neointimal formation with enhancement of adhesion molecules, fibrinogen accumulation and cell proliferation on day 28 after injury. However, intimal thickening and expression of these factors were suppressed in PAI-1 recipients. CONCLUSION: A specific PAI-1 inhibitor prevents thrombus formation and arterial neointimal formation after arterial injury. Thus, PAI-1 plays a critical role in arterial remodeling after mechanical injury. PAI-1 regulation may be useful to prevent thrombus and neointimal formation after PCI.

Activation of IkappaB kinase and NF-kappaB is essential for Helicobacter pylori-induced chronic gastritis in Mongolian gerbils.

The Mongolian gerbil model of Helicobacter pylori infection resembles human gastritis. In this study, we investigated the role of NF-kappaB activation in H. pylori-infected gerbils. Activated macrophages were significantly increased in H. pylori-infected gastric mucosa and were identified as being important cells with potent activation of NF-kappaB, which plays an important part in producing proinflammatory cytokines. Macrophage depletion by the administration of clodronate resulted in milder inflammation in gerbils infected with H. pylori. In macrophages, the inhibition of IkappaB kinase beta (IKKbeta), which is a critical kinase for NF-kappaB activation, resulted in lower proinflammatory cytokine expression caused by heat-killed H. pylori cells. Furthermore, treatment with IKKbeta inhibitor resulted in milder inflammation in gerbils with H. pylori gastritis. Collectively, our data suggest that H. pylori-mediated gastric inflammation critically depends on the efficient recruitment and activation of macrophages, with sufficient NF-kappaB activation.

Inhibition of IkappaB kinase beta restrains oncogenic proliferation of pancreatic cancer cells.

PURPOSE: Pancreatic cancer is characterized by an extremely poor prognosis due to the aggressive disease course and lack of effective therapeutic intervention. IkappaB kinase (IKK), a central kinase for nuclear factor-kappaB (NF-kappaB) activation, is often constitutively activated in pancreatic cancer cells, playing a crucial role in the malignant phenotype and resistance to anti-cancer agents. This study explored how specific inhibition of IKKbeta suppresses oncogenic proliferation of pancreatic cancer cells. EXPERIMENTAL DESIGN: We employed two different approaches, RNA interference-mediated depletion of IKKbeta (IKKbetai) and use of a novel molecularly designed IKKbeta inhibitor IMD-0354 to investigate the effects on the in vitro and in vivo growth and apoptotic response of pancreatic cancer cells. RESULTS: IKKbetai and IMD-0354 efficiently suppressed constitutive NF-kappaB activity and the growth of pancreatic cancer cells in monolayer and soft agar. IMD-0354 induced Annexin V expression, a typical apoptotic cell response. Notably, daily administration of IMD-0354 significantly suppressed tumor growth in NOD/SCID/gamma c(null) (NOG) mice without any deleterious side effect. CONCLUSIONS: These results identify IKKbeta as an attractive molecular target for pancreatic cancer therapy.

Inhibition of NF-{kappa}B improves left ventricular remodeling and cardiac dysfunction after myocardial infarction.

Several studies have demonstrated that NF-kappaB is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-kappaB is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of IkappaB that acts via inhibition of IKK-beta, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group (P < 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV end-diastolic area: vehicle, 74.13 +/- 3.57 mm(2); IMD-0354, 55.00 +/- 3.73 mm(2); P < 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 +/- 0.26; IMD-0354, 2.61 +/- 0.24; P < 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 +/- 14.87 pg/ml; IMD-0354, 110.75 +/- 6.41 pg/ml; P < 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-beta1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-kappaB activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI.

Topical application with a new NF-kappaB inhibitor improves atopic dermatitis in NC/NgaTnd mice.

Growing evidence has demonstrated the crucial role of NF-kappaB activation on disease severity in allergic disorders. In this study, we examined the clinical relevance of a novel NF-kappaB inhibitor, IMD-0354, for atopic dermatitis (AD) by its topical application. To investigate the in vivo efficacy, 1% IMD-0354 ointment was applied daily to NC/NgaTnd mice with severe dermatitis, which served as a model for human AD. During 2 weeks of treatment, scratching behavior decreased and severity of dermatitis reduced in mice treated with IMD-0354 as well as FK506 without diverse effects. Based on histological examinations, the hyperplasia of keratinocytes and infiltration of inflammatory cells were significantly reduced in the skin of IMD-0354-treated mice. The expressions of T-helper 2 cytokines and tumor necrosis factor-alpha at the affected skin sites were downregulated in IMD-0354-treated mice. Furthermore, IMD-0354 suppressed the proliferation of various immunocompetent cells, neurite outgrowth of nerve growth factor-stimulated pheochromocytoma cells, IgE production from splenic B cells, and IgE-mediated activation of mast cells in vitro. IMD-0354 effectively reduced the allergic inflammation in NC/NgaTnd mice in vivo. Thus, a drug that interferes with NF-kappaB activity may provide an alternative therapeutic strategy for the treatment of AD.

A new RXR agonist, HX630, suppresses intimal hyperplasia in a mouse blood flow cessation model.

The nuclear receptor retinoid X receptor (RXR) forms heterodimers with other nuclear receptors and exerts anti-inflammatory effects. RXR is implicated in the progression of arteriosclerosis; however, the effects of selective RXR activation on smooth muscle cell (SMC) proliferation are unknown. We synthesized a novel RXR agonist, HX630, and examined its effect on vascular SMC (VSMC) proliferation. Male C57BL/6 mice (n=15) were subjected to ligation of the left carotid artery and fed 5 or 10 mg/kg/day HX630 for 4 weeks. HX630-fed mice showed significantly suppressed intimal hyperplasia progression compared to that in control mice (0.286+/-0.093 vs. 1.022+/-0.134 intima/media ratio, P<0.05). Immunohistochemistry of the carotid artery showed that HX630 suppressed cytokine and adhesion molecule staining in lesions undergoing intimal thickening. Interleukin (IL)-1beta-induced VSMC proliferation was inhibited by HX630 and the expression of IL-6 mRNA and protein in VSMCs was suppressed. The RXR agonist HX630 exerts antiproliferative effects in VSMCs in vivo and in vitro. Thus, the RXR may serve as a therapeutic target for vascular injury and intimal thickening.