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The title compound, C23H24N4OS, contains a highly asymmetric bifurcated intramolecular hydrogen bond between the hydroxy group and two pyrazole N atoms. The compound associates into centrosymmetric dimers in the crystal through two unique C-H...pi interactions, which are in turn linked into a (6,3)-network through an additional intermolecular C-H...N hydrogen bond.
Reaction of praseodymium(III) chloride with stoichometric quantities of dibenzoylmethane (Hdbm) and hydrotris[3-(2-pyridyl)pyrazol-1-yl]borate (Tp 2py) affords the title complex, [Pr(C24H19BN9)(C15H11O4)2]. The lanthanide ion in this ternary complex exhibits an N6O4 ten-coordinate geometry arising from the five bidentate arms found on the anionic ligands. The structure is entirely different from those found in other lanthanide complexes with the same ligand set.
The title compound, [Cu(C19H26N3O)2], is the first reported complex of the alkylpyrazolone-derived ligand 1-n-hexyl-3-methyl-4-[1-(phenylimino)propyl]-1H-pyrazol-5(4H)-one. The most notable feature is the imine-enol character presented by the ligand due to coordination, in spite of its enamine-ketone structure in the free state. The ligand chelates through N and O atoms, resulting in a square-planar coordination around the CuII atom, which lies on an inversion centre.
The crystal structure of the title compound, C18H23N5O.H2O, shows molecules containing a phenol group linked perpendicularly to a roughly planar fragment comprising two pyrazole rings. Molecules are stacked perpendicular to the [101] direction, with their phenol groups disposed alternately. The molecular packing in the crystal is stabilized by hydrogen bonding involving water molecules.
In response to pancreatic injury and in cell culture, pancreatic stellate cells (PSCs) are transformed ("activated") into highly proliferative myofibroblast-like cells that express alpha-smooth muscle actin and produce extracellular matrix components. Activated PSCs are implicated in the pathogenesis of pancreatic fibrosis and inflammation. We here evaluated the effects of SP600125 (anthra[1,9-cd]pyrazole-6 (2H)-one), an inhibitor of c-Jun NH(2)-terminal kinase (JNK), on the activation of PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype unless otherwise stated. Activation of JNK was determined by Western blotting using anti-phosphospecific JNK and c-Jun antibodies. Activation of transcription factors was determined by electrophoretic mobility shift assay. The effects of SP600125 on the key parameters of activation (chemokine production, collagen production, and proliferation) were examined. The effect of SP600125 on the activation of freshly isolated PSCs in culture also was examined. Interleukin-1beta activated both 46- and 54-kDa JNK, whereas platelet-derived growth factor-BB activated only 46-kDa JNK. SP600125 inhibited interleukin-1beta-induced JNK activity and activator protein-1 activation, but it did not affect the activation of extracellular-regulated kinase, p38 mitogen-activated protein kinase, and nuclear factor-kappaB. SP600125 inhibited platelet-derived growth factor-induced proliferation, inducible monocyte chemoattractant protein-1 production, and serum-induced type I collagen production. Although SP600125 did not inhibit the transformation, it attenuated the proliferation of freshly isolated PSCs in culture. Collectively, our results suggest a role of JNK in the activation of PSCs, and a potential application of JNK inhibitors for the treatment of pancreatic fibrosis and inflammation.
In this study, we investigated the role of c-Jun NH2-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, in lipopolysaccharide (LPS)-stimulated inducible nitric-oxide synthase (iNOS) expression and nitric oxide (NO) production in J774 murine macrophages. Anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), a pharmacological inhibitor of JNK, inhibited phosphorylation of c-Jun with an IC50 of 5 to 10 microM. At the same concentrations, SP600125 inhibited LPS-induced iNOS protein expression and NO production. SP600125 had no effect on the activation of nuclear factor kappaB, which is an important transcription factor for iNOS expression. SP600125 had no significant effect on iNOS mRNA levels if measured 4 h after LPS. In contrast, SP600125 reduced iNOS mRNA levels >90% when measured 8 h after LPS. These data suggest that SP600125 reduced iNOS mRNA stability, and this was confirmed in the mRNA degradation assay using actinomycin D, in which SP600125 reduced the iNOS mRNA half-life from 5 to 2 h. These results show that the JNK pathway is involved in the up-regulation of LPS-induced iNOS expression and NO production by a mechanism related to the stabilization of iNOS mRNA.
The decreased expression of the nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), occurs in response to multiple stimuli in vivo and in cell culture and correlates with various disease states such as hypertension, inflammation, and neurodegenerative disorders. The ability to understand and modulate sGC expression and cGMP levels in any of these conditions could be a valuable therapeutic tool. We demonstrate herein that the c-Jun NH2-terminal kinase JNK II inhibitor anthra[1,9-cd]pyrazol-6(2H)-one (SP-600125) completely blocked the decreased expression of sGCalpha1-subunit mRNA by nerve growth factor (NGF) in PC12 cells. Inhibitors of the ERK and p38 MAPK pathways, PD-98059 and SB-203580, had no effect. SP-600125 also inhibited the NGF-mediated decrease in the expression of sGCalpha1 protein as well as sGC activity in PC12 cells. Other experiments revealed that decreased sGCalpha1 mRNA expression through a cAMP-mediated pathway, using forskolin, was not blocked by SP-600125. We also demonstrate that TNF-alpha/IL-1beta stimulation of rat fetal lung (RFL-6) fibroblast cells resulted in sGCalpha1 mRNA inhibition, which was blocked by SP-600125. Expression of a constitutively active JNKK2-JNK1 fusion protein in RFL-6 cells caused endogenous sGCalpha1 mRNA levels to decrease, while a constitutively active ERK2 protein had no effect. Collectively, these data demonstrate that SP-600125 may influence the intracellular levels of the sGCalpha1-subunit in certain cell types and may implicate a role for c-Jun kinase in the regulation of sGCalpha1 expression.
We describe the pharmacological characteristics of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt). SM-19712 inhibited endothelin converting enzyme (ECE) solubilized from rat lung microsomes with an IC50 value of 42 nM and, at 10 - 100 microM, had no effect on other metalloproteases such as neutral endopeptidase 24.11 and angiotensin converting enzyme, showing a high specificity for ECE. In cultured porcine aortic endothelial cells, SM-19712 at 1 - 100 microM concentration-dependently inhibited the endogenous conversion of big endothelin-1 (ET-1) to ET-1 with an IC50 value of 31 microM. In anesthetized rats, either intravenous (1-30 mg/kg) or oral (10-30 mg/kg) administration of SM-19712 dose-dependently suppressed the pressor responses induced by big ET-1. In acute myocardial infarction of rabbits subjected to coronary occlusion and reperfusion, SM-19712 reduced the infarct size, the increase in serum concentration of ET-1 and the serum activity of creatinine phosphokinase. The present study demonstrates that SM-19712 is a structurally novel, nonpeptide, potent and selective inhibitor of ECE, and SM-19712 is a valuable new tool for elucidating the pathophysiological role of ECE.
New bis[6-phenyl-4-methyl-3-substituted-pyrazo[4,5-d] pyrazol-1-yl]thioketones have been obtained in good yield by the reaction of thiocarbohydrazine with 1-phenyl-3-methyl-4-acetyl/benzoyl-pyrazol-5-one, followed by cyclization of the intermediate. The new compounds exhibit excellent antimicrobial activity.
The pharmacokinetics of latamoxef and CPW 86-363, a novel carboxy-pyrazol-cephalosporin, were evaluated in healthy volunteers after intravenous bolus injection of 1 g. Based on concentration-time courses in serum both cephalosporins showed similar distribution properties, although CPW 86-363 was eliminated significantly faster. The route of elimination of latamoxef was mainly via the urine, whereas CPW 86-363 was also excreted into the bile. N-methylthiotetrazole, which is the common side chain in position 3 of both cephalosporins, was found in the serum as well as in the urine. Its rate and extent of formation was higher for latamoxef than for CPW 86-363 and depends rather on the instability of the parent compound than on metabolic transformation. This is supported by studies on the in vitro degradation of both derivatives. The relevance of these findings are discussed in view of secondary coagulopathies, which are associated with cephalosporins having a N-methylthiotetrazole side chain.
Adult male Sprague-Dawley rats were injected subcutaneously (s.c.) for 21 days either with the synthetic steroid 17 beta-methoxy-17-methyl-(5 alpha)-1 H'-androstane-(3,2-c) pyrazole (17MM) at two dose levels (0.1 and 1 mg/kg/day) or with the vehicle used to dilute the steroid. At autopsy, caput epididymes and ventral prostates were removed and incubated in vitro. The effect on the 5 alpha-reductase (5 alpha-R) activity was evaluated by measuring the amounts of DHT formed from 14C-testosterone (14C-T) used as the substrate. The in vivo administration of 17MM at the dose of 0.1 mg/kg/day resulted in a significant decrease in the formation of DHT at the level of the epididymis, while there was no effect on the prostate. The dose of 1 mg/kg/day did not induce any modification in the formation of DHT in either organ. The determination of serum LH showed that the treatment with either dose did not alter serum LH titers. These findings suggest that the in vivo treatment with 17MM lowers the in vitro formation of DHT from T at the epididymal, but not at the prostatic level and consequently suggests a selective inhibitory effect of 17MM on the 5 alpha-R present in the epididymis.
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