SB 239063

SB 239063 is a potent and selective p38 MAP kinase inhibitor (IC50 = 44 nM for p38α). SB 239063 displays > 220-fold selectivity over ERK, JNK1 and other kinases; ~ 3-fold more selective than SB 203580. SB 239063 reduces inflammatory cytokine production and is neuroprotective following oral administration in vivo.

SB-239063, a potent and selective inhibitor of p38 map kinase: preclinical pharmacokinetics and species-specific reversible isomerization.[Pubmed:11683250]

Pharm Res. 2001 Sep;18(9):1336-44.

PURPOSE: A series of studies was conducted to evaluate the preclinical pharmacokinetics of SB-239063 (trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-[(2-methoxy)pyrimidin-4-yl] imidazole), a potent and selective p38 MAP kinase inhibitor. METHODS: SB-239063 was administered both i.v. and p.o. in the rat, dog, cynomolgus monkey, and rhesus monkey, with standard pharmacokinetic parameters generated from the concentration vs. time data. RESULTS: Initial rat studies suggested possible nonlinear disposition, however, assay refinement revealed an in vivo trans-cis isomerization of SB-239063 to a metabolite with nearly identical chromatographic and mass spectral properties. SB-239063 exhibited low to moderate clearance and good bioavailability in the rat and dog, but poor bioavailability in the cynomolgus monkey. Substantial in vivo trans-cis isomerization occurred in the rat and cynomolgus monkey, but occurred to a far lesser extent in the dog. The isomerization reaction was reversible, with a recycled fraction of 0.20 and 0.0003 in the rat and cynomolgus monkey, respectively. In the rhesus monkey, bioavailability was also poor. but no in vivo isomerization was observed. Conclusions. These studies demonstrate the necessity of exercising vigilance in conducting high-throughput analytical method development, and the importance of using a variety of preclinical species when evaluating the disposition of new drug candidates.

SB 239063, a novel p38 inhibitor, attenuates early neuronal injury following ischemia.[Pubmed:11172750]

Brain Res. 2001 Feb 16;892(1):70-7.

The aim of the present study was to evaluate p38 MAPK activation following focal stroke and determine whether SB 239063, a novel second generation p38 inhibitor, would directly attenuate early neuronal injury. Following permanent middle cerebral artery occlusion (MCAO), brains were dissected into ischemic and non-ischemic cortices and Western blots were employed to measure p38 MAPK activation. Neurologic deficit and MR imaging were utilized at various time points following MCAO to monitor the development and resolution of brain injury. Following MCAO, there was an early (15 min) activation of p38 MAPK (2.3-fold) which remained elevated up to 1 h (1.8-fold) post injury compared to non-ischemic and sham operated tissue. Oral SB 239063 (5, 15, 30, 60 mg/kg) administered to each animal 1 h pre- and 6 h post MCAO provided significant (P<0.05) dose-related neuroprotection reducing infarct size by 42, 48, 29 and 14%, respectively. The most effective dose (15 mg/kg) was further evaluated in detail and SB 239063 significantly (P<0.05) reduced neurologic deficit and infarct size by at least 30% from 24 h through at least 1 week. Early (i.e. observed within 2 h) reductions in diffusion weighted imaging (DWI) intensity following treatment with SB 239063 correlated (r=0.74, P<0.01) to neuroprotection seen up to 7 days post stroke. Since increased protein levels for various pro-inflammatory cytokines cannot be detected prior to 2 h in this stroke model, the early improvements due to p38 inhibition, observed using DWI, demonstrate that p38 inhibition can be neuroprotective through direct effects on ischemic brain cells, in addition to effects on inflammation.

The selective p38 inhibitor SB-239063 protects primary neurons from mild to moderate excitotoxic injury.[Pubmed:12106800]

Eur J Pharmacol. 2002 Jun 28;447(1):37-42.

Inhibition of the p38 mitogen-activated protein kinase (MAP Kinase) pathway reduces acute ischemic injury in vivo, suggesting a direct role for this signaling pathway in a number of neurodegenerative processes. The present study was designed to evaluate further the role of p38 MAP Kinase in acute excitotoxic neuronal injury using the selective p38 inhibitor SB-239063 (trans-1-(4hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl) imidazole). Unlike the widely used p38 inhibitor, SB-203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole), this second generation p38 inhibitor more selectively inhibits p38 MAP Kinase without affecting the activity of other MAP Kinase signaling pathways and provides a more accurate means to selectively assess the role of p38 in excitotoxicity that has not been previously possible. SB-239063 provided substantial protection against cell death induced by either oxygen glucose deprivation (OGD) or magnesium deprivation in cultured neurons. The ability of this compound to block excitotoxicity was not due to direct inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated currents as SB-239063 did not alter NMDA electrophysiological responses. SB-239063 did not protect against a severe excitotoxic insult induced by 60-min exposure to NMDA. However, when tested against a less severe, brief (5 min) NMDA exposure, p38 inhibition provided substantial protection. These data demonstrate that inhibition of p38 MAP Kinase can confer neuroprotection in vitro against mild but not severe excitotoxic exposure, and suggests that other additional pathways/mechanism(s) may be involved in severe excitotoxic cell death.

Effect of the p38 MAPK inhibitor SB-239063 on Lipopolysaccharide-induced psychomotor retardation and peripheral biomarker alterations in rats.[Pubmed:21545800]

Eur J Pharmacol. 2011 Jul 1;661(1-3):49-56.

Lipopolysaccharide (LPS) administration in rats induces a characteristic syndrome termed 'sickness behavior', including profound changes on locomotor activity and circulating stress and inflammatory mediators. The aim of the present investigation was to evaluate whether the behavioral and the peripheral biomarker responses induced by LPS could be modified by acute treatment with the p38 mitogen-activated protein kinase inhibitor SB-239063. Male Sprague-Dawley rats were treated orally either with vehicle or SB-239063 (3, 10 and 30 mg/kg) 1h before an intraperitoneal injection of either saline or LPS 125 mug/kg. Two hours after LPS injection, rats were placed in a novel open field arena for locomotion assessment during both the light and dark periods. Inflammation and stress mediators were evaluated in plasma 2, 3, 5 or 14 h into the dark phase. Pre-treatment with SB-239063 significantly reversed the locomotor deficits induced by LPS injection. Interleukin (IL)-1beta, IL-6, IL-10, Granulocyte-Macrophage-Colony Stimulating Factor, Interferon-gamma, and C-reactive-protein levels were increased significantly by LPS, but not when LPS was preceded by SB-239063 treatment. LPS significantly decreased growth-hormone and Prolactin, and this effect was attenuated by SB-239063. Tumor Necrosis Factor-alpha, Adrenocorticotropic Hormone and Corticosterone levels were significantly higher in LPS-treated rats and were not normalized by SB-239063. Thus, we demonstrate that acute treatment with SB-239063 may have ameliorating effects in early changes of LPS-induced sickness behavior and alteration in the peripheral cytokines/hormones. As such, our procedure may offer an opportunity to test the activity of novel anti-inflammatory compounds on specific symptoms of sickness associated with neuroimmune dysfunctions.

SB 239063, a second-generation p38 mitogen-activated protein kinase inhibitor, reduces brain injury and neurological deficits in cerebral focal ischemia.[Pubmed:11160612]

J Pharmacol Exp Ther. 2001 Feb;296(2):312-21.

The stress-activated mitogen-activated protein kinase (MAPK) p38 has been linked to the production of inflammatory cytokines/mediators/inflammation and death/apoptosis following cell stress. In these studies, a second-generation p38 MAPK inhibitor, SB 239063 (IC(50) = 44 nM), was found to exhibit improved kinase selectivity and increased cellular (3-fold) and in vivo (3- to 10-fold) activity over first-generation inhibitors. Oral SB 239063 inhibited lipopolysaccharide-induced plasma tumor necrosis factor production (IC(50) = 2.6 mg/kg) and reduced adjuvant-induced arthritis (51% at 10 mg/kg) in rats. SB 239063 reduced infarct volume (48%) and neurological deficits (42%) when administered orally (15 mg/kg, b.i.d.) before moderate stroke. Intravenous SB 239063 exhibited a clearance of 34 ml/min/kg, a volume of distribution of 3 l/kg, and a plasma half-life of 75 min. An i.v. dosing regimen that provided effective plasma concentrations of 0.38, 0.75, or 1.5 microg/ml (i.e., begun 15 min poststroke and continuing over the initial 6-h p38 activation period) was used. Significant and dose-proportional brain penetration of SB 239063 was demonstrated during these infusion periods. In both moderate and severe stroke, intravenous SB 239063 produced a maximum reduction of infarct size by 41 and 27% and neurological deficits by 35 and 33%, respectively. No effects of the drug were observed on cerebral perfusion, hemodynamics, or body temperature. Direct neuroprotective effects from oxygen and glucose deprivation were also demonstrated in organotypic cultures of rat brain tissue. This robust in vitro and in vivo SB 239063-induced neuroprotection emphasizes the potential role of MAPK pathways in ischemic stroke and also suggests that p38 inhibition warrants further study, including protection in other models of nervous system injury and neurodegeneration.

SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence.[Pubmed:10734180]

J Pharmacol Exp Ther. 2000 Apr;293(1):281-8.

The anti-inflammatory/antiallergic activity of a novel second-generation p38 mitogen-activated protein kinase inhibitor, SB 239063[trans-1-(4-hydroxycyclohexyl) -4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole], was investigated in vivo and in vitro. SB 239063 had an IC(50) of 44 nM for inhibition of recombinant purified human p38alpha. In lipopolysaccharide-stimulated human peripheral blood monocytes, SB 239063 inhibited interleukin-1 and tumor necrosis factor-alpha production (IC(50) values = 0.12 and 0.35 microM, respectively). A role for p38 kinase in cytokine-associated inflammation in the mouse was shown by p38 activation in the lung and inhibition of lipopolysaccharide-induced tumor necrosis factor-alpha production by SB 239063 (ED(50) = 5.8 mg/kg p.o.). Antiallergic activity was demonstrated by essential abolition (approximately 93% inhibition) of inhaled ovalbumin (OA)-induced airway eosinophilia by SB 239063 (12 mg/kg p.o.), measured by bronchoalveolar lavage (BAL) in OA-sensitized mice. In addition, p38 kinase was found by Western analysis to be activated in guinea pig lung. Administration of SB 239063 (10 or 30 mg/kg p.o.) in conscious guinea pigs markedly reduced ( approximately 50% inhibition) OA-induced pulmonary eosinophil influx, measured by BAL 24 h after antigen. SB 239063 (10 mg/kg b.i.d. p.o.) administered after leukotriene D(4) inhalation, reduced by 60% the persistent airway eosinophilia seen at 4 days. Apoptosis of cultured eosinophils isolated from guinea pig BAL was increased by SB 239063 (1-10 microM) in the presence of interleukin-5. These results indicate that SB 239063 is a potent inhibitor of inflammatory cytokine production, inhibits eosinophil recruitment, in addition to enhancing apoptosis of these cells. Collectively, the results support the potential utility of p38 kinase inhibitors, such as SB 239063, for the treatment of asthma and other inflammatory disorders.

SB 239063 is a potent, selective and orally active p38 MAPK inhibitor, exhibits an IC50 of 44 nM for recombinant purified human p38α, with equipotent inhibitory activity against p38α and p38β. SB 239063 has no effect on p38γ or p38δ. With anti-asthma activity and also be used to enhance memory which is impaired due to aging or medical conditions, such as, AD.

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